COMBINAÇÃO E MÉTODOS PARA MELHORAR AS TERAPIAS COM INIBIDORES DE PONTO DE VERIFICAÇÃO NO TRATAMENTO DO CÂNCER

Abstract

Combinations of (i) conjugates comprising a targeted immune modulator and (ii) one or more immune checkpoint inhibitors; compositions; and methods of use to reprogram M2-like macrophages to M1-like macrophages to reverse the proinflammatory response observed in cancer to an anti-inflammatory response.

Description

[0001] This patent application relates to and claims the priority benefit of U.S. Provisional Patent Application No. 63 / 454,306, filed March 23, 2023. The contents of the earlier application are incorporated by reference in their entirety into this disclosure. TECHNICAL FIELD

[0002] This disclosure relates to methods for increasing the potency of one or more checkpoint inhibitors (compared to the baseline potency of such checkpoint inhibitors) by using one or more compounds comprising a targeting fraction and reprogramming M2-type macrophages to M1-type macrophages. BACKGROUND

[0003] In a normal healthy system, immune checkpoints are surface proteins present to control and prevent any overstimulation of the immune response. Their function is to prevent an immune response from becoming so strong as to destroy healthy cells in the body. In the case of cancer, when the checkpoint protein on a T cell (e.g., programmed cell death protein 1 (PD-1)) interacts with its binding protein on a cell Petition 870250096077, dated 10 / 21 / 2025, page 6 / 378 2 / 297 tumor control points (programmed cell death ligand 1 (PD-L1)), it sends a “shutdown” signal to T cells and suppresses the antitumor immune response. In this way, killer tumor cells within the immune system are unable to kill the tumor because their method of attack is blocked by these checkpoints in the tumor itself.

[0004] Immune checkpoint inhibitors work by inhibiting the binding of checkpoint proteins to their ligands on tumor cells. PD-1, CTLA-4 (cytotoxic T-cell-associated protein 4), LAG3 (T-cell activating protein 3), TIM3 (T-cell immunoglobulin and mucin domain-containing protein 3), TIGIT (T-cell immunoreceptor with Ig and ITIM domains), and VISTA (V-domain suppressor of T-cell activation) are some examples of checkpoint proteins. Checkpoint inhibitor therapy has been approved by the U.S. Food & Drug Administration (FDA) for several types of cancer. Some of the approved checkpoint inhibitors include anti-PD1 antibodies, including Pembrolizumab (Keytruda®) and Nivolumab (Opdivo®), and an anti-CTLA4 antibody called Ipilimumab (Yervoy®).

[0005] There are still some unmet needs in this area of ​​cancer immunotherapy. For example, ~50% of patients with PD-L1-positive tumors exhibit resistance or relapse after PD-1 / PD-L1 checkpoint therapy (Herbst et al., Predictive correlates of response to anti-PD-L1 antibody MPDL3280A in cancer patients, Nature 515(7528): 563-567 (2014)). One of the critical factors behind checkpoint blockade resistance may be the function of myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) (Bai et al., Regulation of the PD1 / PD-L1 pathway and resistance to PD-1 / PD-L1 blockade, Oncotarget 8(66): 110693110707 (2017)). It is known that MDSCs in a tumor microenvironment Petition 870250096077, dated 10 / 21 / 2025, page 7 / 378 3 / 297 contribute to compromising the effectiveness of checkpoint blockade (Meyer et al., Circulating MDSC frequencies correlate with clinical outcome of melanoma patients treated with ipilimumab, Cancer Immunology Immunotherapy 63: 247-57 (2014)). Similarly, TAM reprogramming has been shown to increase the effectiveness of checkpoint blockade (Zhu et al., CSF1 / CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models, Cancer Research 74: 5057-69 (2014)).

[0006] Despite the clear need for cancer prevention and treatment, these conditions remain significant causes of death and suffering worldwide, as there are currently no effective therapeutic cures. Furthermore, when drugs or other therapies are available, such treatments typically employ highly potent drugs that pose a risk of systemic toxicity to the underlying individual because they are poorly selective for the cancer cells of interest. What is needed is an effective treatment that not only interrupts the growth factor cycle initiated by activated (alternatively activated) M2-type macrophages, but can also do so with very high specificity for the cells in question. SUMMARY

[0007] In some cases, activated M2 phenotype macrophages play a role in cancers, such as secreting anti-inflammatory cytokines that activate fibroblasts to synthesize collagen and other extracellular matrix proteins. In certain cases, these macrophages also cause the release of growth factors that are problematic in individuals with cancer. In some cases, macrophages Petition 870250096077, dated 10 / 21 / 2025, page 8 / 378 4 / 297 activated myofibroblasts, derived from tissue-resident macrophages or peripheral blood monocytes, induce fibroblast activation through the secretion of chemokine ligand 18 (CC motif) (CCL18), transforming growth factor-βΐ (TGFpi), and / or platelet-derived growth factor (PDGF). This activation, in some cases, promotes collagen secretion by fibroblasts, which can cause the progression of associated cancer. In advanced stages of many cancers, activated macrophages and myofibroblasts can cross-stimulate each other, resulting in the promotion of cancerous tumor growth (e.g., due to growth factors secreted by activated macrophages) and / or collagen formation in cancerous tumors (e.g., through downstream fibrotic collagen production, which can result in a cancerous tumor that is more difficult to treat by blocking its penetrability by drugs).

[0008] In some embodiments, a compound represented by the formula QLT is provided herein. In some embodiments, Q is a radical of a folate receptor-binding ligand. In some embodiments, L is a ligand. In some embodiments, T is a radical of a Toll-tike receptor (TLR) agonist. In some embodiments, QLT is a pharmaceutically acceptable salt thereof.

[0009] In some embodiments, the ligand is a non-releasable ligand. In some embodiments, the non-releasable ligand is represented by the formula: Petition 870250096077, dated 10 / 21 / 2025, p. 9 / 378 5 / 297

[00010] In some modalities, n is 1-30. In some modalities, n is 1-24. In some modalities, n is 1-12. In some modalities, n is 1-3. In some modalities, n is 12. In some modalities, n is 3.

[00011] In some modalities, w is 0-5. In some modalities, w is 0-2. In some modalities, w is 1.

[00012] Methods for treating an individual with cancer are also provided. In at least one embodiment of a method for treating an individual with cancer, the method comprises administering a first therapy to an individual, wherein the first therapy comprises at least one pharmaceutically acceptable compound, or salt or hydrate thereof, comprising a radical of an immune modulator linked, by means of a ligand, to a folate ligand, or a functional fragment or analogue thereof, or a composition comprising at least one compound and one or more pharmaceutically acceptable carriers, adjuvants, diluents, excipients and / or vehicles, or combinations thereof; and administering a second therapy to the individual, wherein the second therapy comprises one or more immune checkpoint inhibitors.The immune modulator (e.g., radical) or pharmaceutically acceptable salt or hydrate thereof may target a pattern recognition receptor or a damage-associated molecular pattern (DAMP). In certain embodiments, administration of the second therapy to the subject further comprises the administration of a therapeutically effective amount of one or more immune checkpoint inhibitors. In certain embodiments, administration of the first therapy to the subject comprises the administration of a therapeutically effective amount of at least one compound or pharmaceutically acceptable salt or hydrate thereof, or of a composition comprising at least one compound or a salt or hydrate. Petition 870250096077, dated 10 / 21 / 2025, page 10 / 378 6 / 297 pharmaceutically acceptable.

[00013] In at least one embodiment, administration of at least one pharmaceutically acceptable compound or salt or hydrate of the first therapy reprograms subject M2-type macrophages to subject M1-type macrophages and increases the potency of one or more checkpoint inhibitors of the second therapy relative to the baseline potency of one or more checkpoint inhibitors.

[00014] In at least one embodiment of the method of treating a subject with cancer, the immunomodulator (i.e., radical) is or comprises a Toll-like receptor (TLR) 3 agonist, a TLR 7 agonist, a TLR 8 agonist, a TLR 9 agonist, or a TLR 7 / 8 agonist. In certain embodiments of the method of treating a subject with cancer, the immunomodulator radical is or comprises a TLR7 agonist and the ligand is a non-releasable ligand.

[00015] In at least one modality of a method of treating a subject with cancer, at least one compound is Petition 870250096077, dated 10 / 21 / 2025, p. 11 / 378 7 / 297 It is either a pharmaceutically acceptable salt or carbohydrate thereof.

[00016] In at least one modality of a method of treating a subject with cancer, at least one compound has the following formula: It is either a pharmaceutically acceptable salt or carbohydrate thereof. Petition 870250096077, dated 10 / 21 / 2025, p. 12 / 378 8 / 297

[00017] In at least one embodiment of a method for treating a subject with cancer, the immunomodulator (i.e., radical) is or comprises a TLR agonist of Formula X or XX, or is a pharmaceutically acceptable salt or hydrate of Formula X or XX: (XX) where, in Formulas X and XX: Rl is -NH2 or -NH-R1X, R2 is an H, an alkyl, an alkenyl, an alkynyl, an alicyclic, an aryl, a biaryl, a heteroaryl, -NH-R2X, -O-R2X, -S-R2X, or a non-aromatic bicyclic compound with 3 to 10 members containing N, wherein: In Formula X, R3 is -OH, -SH, -NH2, or -NH-R1X; Petition 870250096077, dated 10 / 21 / 2025, page 13 / 378 9 / 297 in Formula XX, X is a CH or an N; and each of RIX, R2X and R2Y is independently selected from the group consisting of a hydrogen (H), an alkyl, an alkenyl, an alkynyl, an alicyclic, an aryl, a biaryl and a heteroaryl.

[00018] In at least one modality of a method of treating a subject with cancer, the compound comprises: Formula (2-1) is either a pharmaceutically acceptable salt or hydrate thereof, wherein, in Formula (2-1): R1, R3, R4 and R5 are each independently an H, an alkyl, an alkoxy, an alkenyl, an alkynyl, an alicyclic, an aryl, a biaryl, a halo, a heteroaryl, -COR2x, R2> (n = 0-30) Y is a point of attachment to the ligand for linking and / or directing at least one compound and comprises an H, -OH, NH2, -NHR2x, -O-R2X, -SO-R2x, -SH, -SO3H, -N3, -CHO, -COOH, Petition 870250096077, dated 10 / 21 / 2025, page 14 / 378 10 / 297 CONH2, -COSH, -COR2x, -SO2NH2, alkenyl, alkynyl, alkoxyl, -NH-CH2NH2, -CONH2, -SO2NH2, -NH-CS-NH2, □ 2k n'r OR each of R2x and R2y is independently selected from the group consisting of H, -OH, -CH2-OH, -NH2, -CH2-NH2, -COOMe, COOH, -CONH2, -COCH3, alkyl, alkenyl, alkynyl, alicyclic, aryl, biaryl and heteroaryl, and each of R2z is independently selected from the group consisting of -NH2, -NR2qR2q', -O-R2q, -SO-R2q and -COR2q, wherein each of R2q and R2q' is independently alkyl or H; and AΑνΛ is a non-aromatic, mono- or bicyclic heterocycle containing N groups of 3 to 10 members; wherein, in Formula 2-1, each of X1, X2 and X3 is independently CRq or N, and each Rq is independently H, halogen or an optionally substituted alkyl; and wherein, in Formula 2-1, n is 0-30 and is 0-4.

[00019] In at least one embodiment of a method for treating an individual with cancer, the individual has, or is at risk of having, cancer or a recurrence of cancer, and the first therapy administration step further comprises administering or applying to the individual a therapeutically effective amount of the product. Petition 870250096077, dated 10 / 21 / 2025, page 15 / 378 11 / 297 less one pharmaceutically acceptable compound, salt, or carbohydrate thereof.

[00020] In at least one embodiment of a method for treating an individual with cancer, at least one pharmaceutically acceptable compound or salt or hydrate of the first therapy is administered to the individual intravenously, orally, intramuscularly, intraperitoneally, topically, or by inhalation.

[00021] In at least one modality of a treatment method for an individual with cancer, the individual's M2-type macrophages comprise myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), or both MDSCs and TAMs.

[00022] In at least one embodiment of the method, the individual has tumors that are positive for programmed death ligand 1 (PD-L1), programmed death 1 (PD-1), or cytotoxic T lymphocyte-associated antigen 4 (CTLA-4).

[00023] In at least one embodiment of the method, at least one component of the first therapy comprises a composition containing one or more pharmaceutically acceptable carriers, adjuvants, diluents, excipients and / or vehicles, or combinations thereof.

[00024] In at least one embodiment of a method for treating an individual with cancer, the method is performed to treat a cancer recurrence in the individual or resistance to checkpoint blockade therapy in the individual. The individual may be a human, a mouse, or any other mammal.

[00025] In certain embodiments of the method for treating an individual with cancer, one or more second-therapy immune checkpoint inhibitors each comprise a small molecule or other agent that disrupts an immune checkpoint of an individual's cell. In certain embodiments of the method, one or more inhibitors of Petition 870250096077, dated 10 / 21 / 2025, page 16 / 378 12 / 297 second-therapy immune checkpoints are each independently selected from the group consisting of pembrolizumab, nivolumab, ipilimumab, cemiplimab, atezolizumab, avelumab, durvalumab, pidilizumab, MEDI0680 monoclonal antibody, REGN2810 monoclonal antibody or AMP-224 fusion protein targeting PD-1, ociperlimab, islelizumab, a combination of ociperlimab and islelizumab, BMS-936559 / MDX-1105, MPDL3280A / RG7446 / atezolizumab, MSB0010718C / avelumab or MEDI4736 / durvalumab, tiragolumab, zimberelimab, tremelimumab, relatlimab, monoclonal antibody IMP321, nivolumab, etigilimab, domvanalimab, tiragolumab (RG6058), vibostolimab, avelumab and durvalumab. In at least one modality of a treatment method for an individual with cancer, one or more checkpoint inhibitors of the second therapy comprise one or more of the following: pembrolizumab, nivolumab and ipilimumab, cemiplimab, atezolizumab, avelumab, durvalumab, or a small molecule or other agent that disrupts an immune checkpoint of an individual's cell.

[00026] In at least one embodiment of a method for treating a subject with cancer, the method further comprises obtaining a biological sample from the subject and quantifying the expression level of one or more biomarkers in the biological sample. In at least one embodiment of a method for treating a subject with cancer, the biological sample is obtained from a quantity of peripheral blood collected from the subject. In at least one embodiment of a method for treating a subject with cancer, the quantification is performed using a process selected from a group consisting of qPCR, mass spectrometry, ELISA, and another modality capable of measuring or quantifying the expression of biomarkers. One or more biomarkers may be, for example, Petition 870250096077, dated 10 / 21 / 2025, page 17 / 378 13 / 297 example, selected from a group consisting of CCL18, Argl, MMP9, TIMP 3, IL-Ιβ, PDGF, TGF£, FR£, hydroxyproline, collagen, TNFa, IFN-γ, CD206, CD 163, IL-6, CXCL10, IFNa and CD86.

[00027] In at least one embodiment of a method of treating a subject with cancer, the method further comprises comparing an expression level of each or more biomarkers with an expression level of such biomarker in a control, wherein the control is a healthy individual or an individual who is not presenting with cancer.

[00028] In at least one embodiment of a method of treating a subject with cancer, the immunomodulator radical is or comprises a TLR agonist with the following formula: in which: Rl is an amine group; R2 is a single -NH- bond; R3 is an H, an alkyl group, a hydroxyl group, or any other substituted group of these; X is CH2, NH, O, or S; and the ligand is attached to R1, R2, or R3. Petition 870250096077, dated 10 / 21 / 2025, page 18 / 378 14 / 297

[00029] In at least one embodiment of a method for treating an individual with cancer, the linker of at least one pharmaceutically acceptable compound or salt or hydrate of the first therapy is a releasable linker. In at least one embodiment of a method for treating an individual with cancer, the linker of at least one pharmaceutically acceptable compound or salt or hydrate of the first therapy is a non-releasable linker. In at least one embodiment of a method for treating a subject with cancer, the linker of at least one pharmaceutically acceptable compound or salt or hydrate of the first therapy comprises a polyethylene glycol (PEG) linker or a PEG-derived linker and is a non-releasable linker.

[00030] In at least one embodiment of a treatment method for a subject with cancer, one or more second-therapy immune checkpoint inhibitors inhibit an immune checkpoint of a selected cell from a group consisting of: PDL1, PD-1, CTLA-4, T-cell activation domain V Ig suppressor (VISTA), lymphocyte activator 3 (LAG3), T-cell immunoglobulin-containing protein 3 (TIM3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), programmed death ligand 2 (PD-L2), indoleamine 2,3-deoxygenase (IDO), arginase-1 (AGR1), B7 family inhibitory ligand B7-H3 (B7-H3), B7 family inhibitory ligand B7-H4 (B7H4), 2B4 (cluster of differentiation 244), B and T lymphocyte attenuator (BTLA), adenosine receptor A2A (A2aR) and / or a member of the killer cell immunoglobulin-like receptor (KIR) family, such as KIRs and C-type lectin receptors,and signal transducer and transcription activator (STAT3).

[00031] In at least one modality of a method of treating an individual with cancer, the first and second therapies are administered simultaneously or sequentially (in any Petition 870250096077, dated 10 / 21 / 2025, page 19 / 378 15 / 297 order). In certain modalities, the administration of at least one pharmaceutically acceptable compound or salt or hydrate of the first therapy activates antitumor cells or an anti-inflammatory signaling cascade in the individual. Antitumor cells may be, for example, T cells, macrophages, or T cells and macrophages.

[00032] Additional methods are provided for increasing the potency of one or more immune checkpoint inhibitors administered to an individual. In certain embodiments, a method for increasing the potency of one or more immune checkpoint inhibitors administered to an individual comprises: administering to the individual one or more pharmaceutically acceptable compounds or salts or hydrates thereof, comprising a radical of an immune modulator linked, via a ligand, to a folate ligand or functional fragment or analogue thereof, wherein the immune modulator radical targets a pattern recognition receptor or DAMP, and bringing a target cell of the individual into contact with one or more pharmaceutically acceptable compounds or salts or hydrates to reprogram the individual's M2-type macrophages into M1-type macrophages.

[00033] In some cases, activated M2 phenotype macrophages play a role in fibrotic diseases, such as through the secretion of anti-inflammatory cytokines that activate fibroblasts to synthesize collagen and other extracellular matrix proteins. In certain cases, these macrophages also cause the release of growth factors that are problematic in individuals with cancer. For example, such growth factors can promote the growth of cancerous tumors. Furthermore, in some cases, macrophages (e.g., concomitantly) release immunosuppressive cytokines. Thus, macrophages may play an important role in Petition 870250096077, dated 10 / 21 / 2025, page 20 / 378 16 / 297 facilitating the establishment and growth of fibrotic diseases and / or cancer.

[00034] In some cases, activated macrophages, which derive from tissue-resident macrophages or peripheral blood monocytes, induce fibroblast activation through the secretion of chemokine ligand 18 (CC motif) (CCL18), transforming growth factor-β1 (TGFβ1), and / or platelet-derived growth factor (PDGF). This activation, in some cases, promotes collagen secretion by fibroblasts, which may cause the advancement of associated cancer. In advanced stages of many cancers, activated macrophages and myofibroblasts can mutually stimulate each other, resulting in the promotion of cancerous tumor growth (e.g., due to growth factors secreted by activated macrophages) and / or collagen formation in cancerous tumors (e.g., through downstream fibrotic collagen production, which may result in a more difficult-to-treat cancerous tumor by blocking drug penetrability).

[00035] In certain embodiments of the method for increasing the potency of one or more immune checkpoint inhibitors administered to an individual, the immune modulator radical is or comprises a TLR 3 agonist, a TLR 7 agonist, a TLR 8 agonist, a TLR 9 agonist, or a TLR 7 / 8 agonist. In certain embodiments of the method for increasing the potency of one or more immune checkpoint inhibitors administered to an individual, the immune modulator radical is or comprises a TLR 7 agonist and the ligand is a releasable ligand. In certain embodiments of the method for increasing the potency of one or more immune checkpoint inhibitors administered to an individual, the immune modulator radical is or comprises a TLR 7 agonist and the ligand is a non-releasable ligand.

[00036] In certain modalities of the method for increasing power Petition 870250096077, dated 10 / 21 / 2025, page 21 / 378 17 / 297 of one or more immune checkpoint inhibitors administered to an individual, one or more compounds is or comprises a structure represented by: It is either a pharmaceutically acceptable salt or carbohydrate thereof.

[00037] The ligand may be a non-releasable ligand. The ligand may be a releasable ligand. In certain modalities, the cancerous disease state comprises a recurrence of cancer.

[00038] In some embodiments, a compound represented by the formula QLT, or a pharmaceutically acceptable salt or hydrate thereof, is provided herein. In some embodiments, Q is a radical of a folate receptor-binding ligand. In some embodiments, L is a ligand. In some embodiments, T is a radical of a TLR agonist. In some embodiments, QLT is a salt. Petition 870250096077, dated 10 / 21 / 2025, p. 22 / 378 18 / 297 pharmaceutically acceptable of the same.

[00039] In some embodiments, the ligand is a non-releasable ligand. In some embodiments, the non-releasable ligand is represented by the formula:

[00040] In some modalities, n is 1-30. In some modalities, n is 1-24. In some modalities, n is 1-12. In some modalities, n is 1-3. In some modalities, n is 12. In some modalities, n is 3.

[00041] In some modalities, w is 0-5. In some modalities, w is 0-2. In some modalities, w is 1.

[00042] In some modalities, the TLR agonist is a TLR7 agonist. In some modalities, the TLR agonist radical has a structure represented by Formula X: CX).

[00043] In some embodiments, RI is -NH2 or -NH-R1X. In some embodiments, R2 is an H, an alkyl, an alkenyl, an alkynyl, Petition 870250096077, dated 10 / 21 / 2025, p. 23 / 378 19 / 297 an alicyclic, an aryl, a biaryl, a heteroaryl, -NH-R2X, -O-R2X, -SR2X —N R2X, or In some sports, each of RIX, R2X, and R2Y are independently selected from the group consisting of a hydrogen (H), an alkyl, an alkenyl, an alkynyl, an alicyclic, an aryl, a biaryl, and a heteroaryl. In some embodiments, it is a non-aromatic mono- or bicyclic heterocycle containing nitrogen (N) with 3 to 10 members. In some embodiments, R3 is -OH, -SH, -NH2, or -NH-R1X. In some embodiments, RI is -NH2 or NH-R1X; R2 is an H, an alkyl, an alkenyl, an alkynyl, an alicyclic, an aryl, a biaryl, a heteroaryl, -NH-R2X, -O-R2X, -S- R2X Rx —N —N R2X, or ; each of RIX, R2X and R2Y is selected independently from the group consisting of an H, an alkyl, an alkenyl, an alkynyl, an alicyclic, an aryl, a biaryl and a heteroaryl; It is a non-aromatic mono- or bicyclic heterocycle with 3 to 10 members containing N; and R3 is -OH, -SH, -NH2, or -NH-R1X.

[00044] In some modalities, the TLR agonist radical has a structure represented by Formula XX: Petition 870250096077, dated 10 / 21 / 2025, p. 24 / 378 20 / 297 R1 can be -NH2 or -NH-R1X. R2 can be an H, an alkyl, an alkenyl, an alkynyl, an alicyclic, an aryl, a biaryl, a heteroaryl, -NH-R2X, R2XR2X —N — NJ R ×Ã' R -O-R2X, -S-R2X, or 2Y. In some embodiments, each of R1X, R2X, and R2Y is independently selected from the group consisting of an H, an alkyl, an alkenyl, an alkynyl, an alicyclic, an aryl, a biaryl, and a heteroaryl. In some embodiments, it is a non-aromatic mono- or bicyclic heterocycle containing N from 3 to 10 members. In some embodiments, X is CH, CR2, or N. In some embodiments, R1 is -NH2 or -NH-R1X; R2 is an H, an alkyl, an alkenyl, an alkynyl, an alicyclic, an aryl, a biaryl, a heteroaryl, -NH-R2X, -O-R2X, -S-R2X, or R2Y; Each of RIX, R2X, and R2Y is selected independently from the group consisting of an H, an alkyl, an alkenyl, an alkynyl, an alicyclic, an aryl, a biaryl, and a heteroaryl; It is a non-aromatic monocyclic or bicyclic heterocycle containing N groups of 3 to 10 members; and X is CH, CR2 or No. Petition 870250096077, dated 10 / 21 / 2025, p. 25 / 378 21 / 297

[00045] In some forms, the TLR7 agonist radical has a structure represented by Formula XXX:

[00046] In some embodiments, the compound further comprises an Ln linker between the targeting moiety and the immune modulator or its pharmaceutically acceptable salt, wherein the Ln linker is configured to prevent the release of a free form of the TLR7 agonist, en is an integer equal to or less than 50. In some embodiments, the Ln linker comprises PEG or a PEG derivative, n is an integer selected in the range of 1 to 32, and the folate receptor-binding linker radical is a folate receptor-binding β (Eββ) linker.

[00047] In some embodiments, the compound has a structure represented by: Petition 870250096077, dated 10 / 21 / 2025, p. 26 / 378 22 / 297 It is either a pharmaceutically acceptable salt or carbohydrate thereof.

[00048] In some embodiments, the compound has a structure represented by: Petition 870250096077, dated 10 / 21 / 2025, p. 27 / 378 23 / 297 It is either a pharmaceutically acceptable salt or carbohydrate thereof.

[00049] In some embodiments, the compound has a structure represented by: Petition 870250096077, dated 10 / 21 / 2025, p. 28 / 378 24 / 297 is either a pharmaceutically acceptable salt or hydrate thereof.

[00050] In some forms, the compound has a structure represented by: It is either a pharmaceutically acceptable salt or carbohydrate thereof.

[00051] In some embodiments, a pharmaceutical composition comprising one or more of the compounds described herein or a pharmaceutically acceptable salt or hydrate thereof is provided herein, wherein the immunomodulator radical is or comprises a TLR7 agonist with a structure represented by Formula XX.

[00052] In certain cases, a method is provided here for treating an individual suffering from a fibrotic disease state or cancer, the method comprising contacting a cell of the individual with at least one compound comprising a compound or salt or hydrate Petition 870250096077, dated 10 / 21 / 2025, page 29 / 378 25 / 297 pharmaceutically acceptable as described herein, wherein the immunomodulator radical comprises a TLR 3, 7, 8, 9 or 7 / 8 agonist.

[00053] In some embodiments, a compound comprising a folate ligand or a functional fragment or analogue thereof linked to a TLR agonist via a ligand, the TLR agonist having the following formula or a pharmaceutically acceptable salt thereof is provided here:

[00054] In some embodiments, RI is an amine group, R2 is a single -NH- bond, and R3 is an H, an alkyl, a hydroxyl group, or any other substituted group thereof, X is a CH2, NH, oxygen (O), or sulfur (S), and the ligand is attached to RI, R2, or R3.

[00055] In some embodiments, a pharmaceutical composition is provided herein comprising the compound of any of the formulas provided herein, wherein the ligand comprises a PEG ligand or a PEG-derived ligand and is a non-releasable ligand linked to R3 or is a releaseable ligand linked to RI, R2 or R3.

[00056] In some embodiments, the pharmaceutically acceptable salt is selected from hydrobromide, citrate, trifluoroacetate, ascorbate, hydrochloride, tartrate, triflate, maleate, mesylate, formate, acetate or fumarate.

[00057] Combinations for use employing any of the compounds / conjugates described herein are also provided. In certain embodiments, the combination is for use in the treatment of cancer in Petition 870250096077, dated 10 / 21 / 2025, page 30 / 378 26 / 297 an individual and the combination comprises: a first medicinal product comprising and a second medicinal product. The first medicinal product may comprise at least one pharmaceutically acceptable compound or salt or hydrate thereof comprising a radical of an immune modulator linked, via a ligand, to a folate ligand or functional fragment or analogue thereof, wherein the radical of the immune modulator targets a pattern recognition receptor or a DAMP, or a composition comprising at least one pharmaceutically acceptable compound or salt or hydrate thereof, and one or more pharmaceutically acceptable carriers, adjuvants, diluents, excipients and / or vehicles. In addition, the second medicinal product may comprise one or more immune checkpoint inhibitors.

[00058] In the combination, the immunomodulator radical of the first drug may comprise a TLR 3 agonist, a TLR 7 agonist, a TLR 8 agonist, a TLR 9 agonist, or a TLR 7 / 8 agonist (i.e., a TLR 3, 7, 8, 9, or 7 / 8 agonist). At least one compound of the first drug in the combination may have the following formula:. the A* HO0 H2N NN or it may be a pharmaceutically acceptable salt or hydrate thereof. In certain embodiments, the immunomodulator radical comprises a TLR agonist of Formula X or XX, or is a pharmaceutically acceptable salt or hydrate of Formula X or XX: Petition 870250096077, dated 10 / 21 / 2025, p. 31 / 378 21j2W (XX) where, in Formulas X and XX: RI is -NH2 or -NH-R1X, R2 is an H, an alkyl, an alkenyl, an alkynyl, an alicyclic, an aryl, a biaryl, a heteroaryl, -NH-R2X, -O-R2X, -S-R2X, R2X —N RiY It is a non-aromatic monocyclic or bicyclic heterocycle containing N of 3 to 10 members, where: In Formula X, R3 is -OH, -SH, -NH2, or -NH-R1X; Petition 870250096077, dated 10 / 21 / 2025, p. 32 / 378 28 / 297 in Formula XX, X is a CH or an N; and each of RIX, R2X and R2Y is independently selected from the group consisting of an H, an alkyl, an alkenyl, an alkynyl, an alicyclic, an aryl, a biaryl and a heteroaryl.

[00059] In certain embodiments of the combination, at least one component of the first medicinal product comprises: Formula (2-1) is either a pharmaceutically acceptable salt or hydrate thereof, wherein, in Formula 2-1: R1, R3, R4 and R5 are each independently H, an alkyl, an alkoxy, an alkenyl, an alkynyl, an alicyclic, an aryl, a biaryl, a halo, a heteroaryl, -COR2x, or R2 is an H, -OH, -NH2, -NHR2x, N3, -NH-CH2-NH2, -CONH2, Petition 870250096077, dated 10 / 21 / 2025, p. 33 / 378 29 / 297 -SO2NH2, -NH-CS-NH2, or Y is a ligand attachment point and / or a targeting ligand of at least one compound and comprises H, -OH, NH2, -NHR2x, -O-R2X, -SO-R2x, -SH, -SO3H, -N3, -CHO, -COOH, CONH2, -COSH, -COR2x, -SO2NH2, alkenyl, alkynyl, alkoxyl, -NH-CH2NH2, -CONH2, -SO2NH2, -NH-CS-NH2, or Each of R2x and R2y is independently selected from the group consisting of H, -OH, -CH2-OH, -NH2, -CH2-NH2, -COOMe, COOH, -CONH2, -COCH3, alkyl, alkenyl, alkynyl, alicyclic, aryl, biaryl and heteroaryl, and each of R2z is independently selected from the group consisting of -NH2, -NR2qR2q', -O-R2q, -SO-R2q and -COR2q; wherein each of R2q and R2q' is independently alkyl or H; and is a 3 to 10 membered N-containing heterocycle that is non-aromatic, mono- or bicyclic; where, in Formula 2-1, each of X1, X2 and X3 is independently CRq or N, and each Rq is independently H, halogen or an optionally substituted alkyl; and Petition 870250096077, dated 10 / 21 / 2025, p. 34 / 378 30 / 297 where, in Formula 2-1, n is 0-30 and is 0-4.

[00060] In certain embodiments of the combination, the immunomodulator radical of the first drug comprises a TLR agonist with the following formula or a pharmaceutically acceptable salt thereof: in which: RI is an amine group. R2 is a single -NH- bond. R3 is an H, an alkyl group, a hydroxyl group, or any other substituted group thereof. X is CH2, NH, O, or S, and the ligand is attached to RI, R2, or R3.

[00061] In certain combination forms, at least one component of the first drug is Petition 870250096077, dated 10 / 21 / 2025, p. 35 / 378 31 / 297 It is either a pharmaceutically acceptable salt or carbohydrate thereof.

[00062] The ligand of the first drug in the combination may be a releasable ligand. The ligand of the first drug in the combination may be a non-releasable ligand. The ligand of the first drug in the combination may be or comprise a PEG ligand or a PEG-derived ligand and is a non-releasable ligand.

[00063] In certain combination modalities, the subject has a tumor that is positive for PD-L1, PD-1, or CTLA-4.

[00064] In certain embodiments, one or more second-drug immune checkpoint inhibitors comprise a small molecule or other agent that disrupts an immune checkpoint of a subject cell. In certain combination embodiments, one or more second-drug checkpoint inhibitors Petition 870250096077, dated 10 / 21 / 2025, page 36 / 378 32 / 297 medicines are each independently selected from the group consisting of pembrolizumab, nivolumab, ipilimumab, cemiplimab, atezolizumab, avelumab, durvalumab, pidilizumab, monoclonal antibody MEDI-0680, monoclonal antibody REGN2810 or fusion protein AMP-224 targeting PD-1, ociperlimab, islelizumab, a combination of ociperlimab and islelizumab, BMS-936559 / MDX-1105, MPDL3280A / RG7446 / atezolizumab, MSB0010718C / avelumab or MEDI4736 / durvalumab, tiragolumab, zimberelimab, tremelimumab, relatlimab, monoclonal antibody IMP321, nivolumab, etigilimab, domvanalimab, tiragolumab (RG6058), vibostolimab, avelumab and durvalumab.

[00065] In certain embodiments of the combination, one or more immune checkpoint inhibitors of the second drug are one or more agents that bind to or inhibit an immune checkpoint of a selected cell from a group consisting of PD1, PD-L1, CTLA-4, VISTA, LAG3, TIM3, TIGIT, PD-L2, IDO, AGR1, B7-H3, B7-H4, 2B4, BTLA, A2aR and / or a member of the KIR family, such as KIRs and C-type lectin receptors, and STAT3.

[00066] Cancer can be or comprise a cold tumor, a hot tumor, or an immune desert tumor.

[00067] In certain embodiments, any of the combinations described herein may be used to increase the potency of one or more immune checkpoint inhibitors administered to a subject with cancer and / or to treat cancer.

[00068] In some embodiments, a method is provided for preventing or treating a cancerous disease state, comprising contacting a cell with at least one compound (for example, any compound provided by a formula provided herein) comprising an immunomodulator or a pharmaceutically available salt. Petition 870250096077, dated 10 / 21 / 2025, page 37 / 378 33 / 297 acceptable of the same linked, via a ligand, to a folate ligand or functional fragment or analogue thereof, wherein the immunomodulator or a pharmaceutically acceptable salt thereof targets a pattern recognition receptor or a DAMP. In some embodiments, the cell comprises a cell from a subject who has, or is at risk of having, a fibrotic disease state, and the contact of the cell with at least one compound further comprises the administration or application to the subject of a therapeutically effective amount of at least one compound. In some embodiments, the subject is a patient with IPF and at least one compound is administered to the subject intravenously, orally, intramuscularly, intraperitoneally, topically, or by inhalation. In some embodiments, the fibrotic disease state comprises IPF or a fibrotic disease of the liver, skin, bladder, heart, pancreas, prostate, or kidneys.

[00069] In some embodiments, the method further comprises obtaining, or having obtained, a sample from the subject; quantifying the expression level of one or more biomarkers in the sample, each of the one or more biomarkers selected from the group consisting of CCL18, Arg1, MMP9, TIMP3, IL-1β, hydroxyproline, collagen, PDGF, TGF3, FR3, TNFα, IFN-γ, CD206, CD163, CD86, IL-6, CXCL10 and IFNα; comparing the expression level of each of the one or more biomarkers in the sample with the expression level of that biomarker in a control; and administering or having administered to the subject a therapeutically effective amount of an unconjugated agonist or inhibitor if CCL18, Arg1, MMP9, TIMP 3, IL-Iβ, PDGF, TGF3, FR3, CD206, CD163, hydroxyproline, or collagen is upregulated relative to the control expression level, or TNFα, IFN-γ, IL-6, CXCL10, IFNα, or CD86 is downregulated or not expressed relative to the control expression level.

[00070] In some embodiments, folate binder or fragment Petition 870250096077, dated 10 / 21 / 2025, pp. 38 / 378 34 / 297 functional or analog thereof is specific for FR3 and binds to an FR3 on the cell. In some embodiments, a method is provided for treating an individual exhibiting a cancerous disease state (e.g., cancer or cancer recurrence / relapse), comprising increasing the potency of one or more checkpoint inhibitors administered to the individual by administering one or more compounds (or pharmaceutically acceptable salts or hydrates thereof) comprising a targeting fraction (e.g., a folate ligand or functional fragment or analog thereof) linked, via a ligand, to a radical of an immune modulator or a pharmaceutically acceptable salt thereof (e.g., any TLR agonist, including, without limitation, a TLR 3, 7, 8, 9 or 7 / 8 agonist), wherein the targeting fraction targets a pattern recognition receptor or a DAMP of a cell.In certain embodiments, contact of a target cell of the subject with one or more pharmaceutically acceptable compounds or salts or hydrates thereof reprograms M2-type macrophages of the subject to M1-type macrophages. In at least one exemplary embodiment, the immunomodulator radical or pharmaceutically acceptable salt thereof is a TLR7 agonist and the ligand is a releasable ligand. In at least one additional embodiment, the ligand is a non-releasable ligand.

[00071] In certain embodiments, the administration of at least one pharmaceutically acceptable compound or salt or hydrate thereof (e.g., of the first therapy or first drug) activates antitumor cells or an anti-inflammatory signaling cascade in the subject. In at least one embodiment, such antitumor cells are T cells. Additionally or alternatively, such antitumor cells may be macrophages. Petition 870250096077, dated 10 / 21 / 2025, page 39 / 378 35 / 297 DESCRIPTION OF THE DRAWINGS

[00072] The embodiments disclosed and other features, advantages and aspects contained herein, and the question of how to obtain them, will become evident in light of the following detailed description of several exemplary embodiments of the present disclosure. Such detailed description will be better understood when considered in conjunction with the accompanying drawings, in which:

[00073] FIG. 1A shows the chemical structure of an exemplary compound with a targeting moiety (e.g., a folate receptor ligand) linked to an immune modulator (e.g., a radical of a Toll-like receptor (TLR) 7 (TLR7) agonist) via a non-releasable ligand (e.g., comprising a polyethylene glycol (PEG) backbone).

[00074] FIG. 1B shows the chemical structure of an exemplary compound with a targeting moiety (e.g., a folate receptor ligand) linked to an immune modulator (e.g., a TLR7 agonist radical) via a releasable ligand (e.g., comprising a disulfide moiety in its main structure), as well as an exemplary drug release mechanism.

[00075] FIG. 1C shows the chemical structure of example compounds provided here.

[00076] FIG. 1D shows how checkpoint proteins, such as programmed death ligand 1 (PD-L1) in tumor cells and programmed cell death protein 1 (PD-1) in T cells, help keep immune responses under control. Binding of PD-L1 to PD-1 prevents T cells from killing tumor cells in the body (left panel). Blocking the binding of PD-L1 to PD-1 with an inhibitor of Petition 870250096077, dated 10 / 21 / 2025, page 40 / 378 36 / 297 immune checkpoint (anti-PD-L1 or anti-PD-1) allows T cells to kill tumor cells (right panel).

[00077] FIG. 2 shows a representative flowchart of methods for treating an individual who suffers from, or is at risk of suffering from, a fibrotic disease or cancer.

[00078] FIG. 3A shows graphical data of various marker levels measured in human M2-type macrophages when in contact with an exemplary free (non-targeted) TLR7 agonist or an exemplary targeted TLR7 agonist (e.g., with a folate receptor-binding ligand) at various concentrations for each compound. Each value represents the mean ± SD for each group; #P<0.05, ##P<0.01, ###P<0.005, ####P<0.0001; treated groups versus untreated M2 group by Dunnett's multiple comparison test. FIG. 3B shows graphical data of various marker levels measured in human M2-type macrophages when in contact with an exemplary free (non-targeted) TLR7 agonist or an exemplary targeted TLR7 agonist (e.g., with a folate receptor-binding ligand) at various concentrations for each compound. Each value represents the mean ± SD for each group; #P<0.05, ##P<0.01, ###P<0.005, ####P<0.000l; treated groups versus untreated M2 group by Dunnett's multiple comparison test. FIG. 3C shows graphical data of various marker levels measured in human M2-type macrophages when in contact with an exemplary free (non-targeted) TLR7 agonist or an exemplary targeted TLR7 agonist (e.g., with a folate receptor-binding ligand) at various concentrations for each compound. Each value represents the mean ± SD for each group; #P<0.05, ##P<0.01, ###P<0.005, ####P<0.000l; treated groups versus untreated M2 group. Petition 870250096077, dated 10 / 21 / 2025, p. 41 / 378 37 / 297 by Dunnett's multiple comparison test. FIG. 3D shows graphical data of various marker levels measured in human M2-type macrophages when in contact with an exemplary free (non-targeted) TLR7 agonist or an exemplary targeted TLR7 agonist (e.g., with a folate receptor-binding ligand) at various concentrations for each compound. Each value represents the mean ± SD for each group; #P<0.05, ##P<0.01, ###P<0.005, ####P<0.0001; treated groups versus untreated M2 group by Dunnett's multiple comparison test. FIG. 3E shows graphical data of various marker levels measured in human M2-type macrophages when in contact with an exemplary free (non-targeted) TLR7 agonist or an exemplary targeted TLR7 agonist (e.g., with a folate receptor-binding ligand) at various concentrations for each compound. Each value represents the mean ± SD for each group; #P<0.05, ##P<0.01, ###P<0.005, ####P<0.0001; treated groups versus untreated M2 group by Dunnett's multiple comparison test. FIG. 3F shows graphical data of various marker levels measured in human M2-type macrophages when in contact with an exemplary free (non-targeted) TLR7 agonist or an exemplary targeted TLR7 agonist (e.g., with a folate receptor-binding ligand) at various concentrations for each compound. Each value represents the mean ± SD for each group; #P<0.05, ##P<0.01, ###P<0.005, ####P<0.0001; treated groups versus untreated M2 group by Dunnett's multiple comparison test.

[00079] FIG. 4A shows representative graphical data of several Petition 870250096077, dated 10 / 21 / 2025, p. 42 / 378 38 / 297 marker levels measured in M2 macrophages that were incubated with various concentrations of exemplary free or targeted TLR7 agonists for 2 hours (FIGS. 4A-4E) or 46 hours (FIGS. 5A-5D). Each value represents the mean ± standard deviation for each group; #P<0.05, ##P<0.01, ###P<0.005, ####P<0.0001; groups treated with Compound 1A and Compound 1B in FIGS. 4A-5D versus untreated M2 group by Dunnett's multiple comparison test. FIG. 4B shows representative graphical data of various marker levels measured in M2 macrophages that were incubated with various concentrations of exemplary free or targeted TLR7 agonists for 2 hours (FIGS. 4A-4E) or 46 hours (FIGS. 5A-5D). Each value represents the mean ± standard deviation for each group; #P<0.05, ##P<0.01, ###P<0.005, ####P<0.0001; groups treated with Compound 1A and Compound 1B in FIGS. 4A-5D versus untreated M2 group by Dunnett's multiple comparison test. FIG. 4C shows representative graphical data of various marker levels measured in M2 macrophages that were incubated with various concentrations of exemplary free or targeted TLR7 agonists for 2 hours (FIGS. 4A-4E) or 46 hours (FIGS. 5A-5D). Each value represents the mean ± standard deviation for each group; #P<0.05, ##P<0.01, ###P<0.005, ####P<0.0001; groups treated with Compound 1A and Compound 1B in FIGS. 4A-5D versus untreated M2 group by Dunnett's multiple comparison test. FIG. 4D shows representative graphical data of various marker levels measured in M2 macrophages that were incubated with various concentrations of exemplary free or targeted TLR7 agonists for 2 hours (FIGS. 4A-4E) or 46 hours (FIGS. 5A-5D). Petition 870250096077, dated 10 / 21 / 2025, p. 43 / 378 39 / 297 Each value represents the mean ± standard deviation for each group; #P<0.05, ##P<0.01, ###P<0.005, ####P<0.0001; groups treated with Composite 1A and Composite 1B in FIGS. 4A-5D versus untreated group M2 by Dunnett's multiple comparison test. FIG. 4E shows representative graphical data of various marker levels measured in M2 macrophages that were incubated with various concentrations of exemplary free or targeted TLR7 agonists for 2 hours (FIGS. 4A-4E) or 46 hours (FIGS. 5A-5D). Each value represents the mean ± standard deviation for each group; #P<0.05, ##P<0.01, ###P<0.005, ####P<0.0001; groups treated with Compound 1A and Compound 1B in FIGS. 4A-5D versus untreated M2 group by Dunnett's multiple comparison test. FIG. 5A shows representative graphical data of various marker levels measured in M2 macrophages that were incubated with various concentrations of exemplary free or targeted TLR7 agonists for 2 hours (FIGS. 4A-4E) or 46 hours (FIGS. 5A-5D). Each value represents the mean ± standard deviation for each group; #P<0.05, ##P<0.01, ###P<0.005, ####P<0.0001; groups treated with Compound 1A and Compound 1B in FIGS. 4A-5D versus untreated M2 group by Dunnett's multiple comparison test. Figure 5B shows representative graphical data of various marker levels measured in M2 macrophages that were incubated with various concentrations of exemplary free or targeted TLR7 agonists for 2 hours (Figs. 4A-4E) or 46 hours (Figs. 5A-5D). Each value represents the mean ± standard deviation for each group; #P<0.05, ##P<0.01, ###P<0.005, ####P<0.0001; groups treated with Compound 1A and Compound 1B in Figs. 4A-5D versus untreated M2 group. Petition 870250096077, dated 10 / 21 / 2025, p. 44 / 378 40 / 297 Dunnett multiple comparison test. FIG. 5C shows representative graphical data of various marker levels measured in M2 macrophages that were incubated with various concentrations of exemplary free or targeted TLR7 agonists for 2 hours (FIGS. 4A-4E) or 46 hours (FIGS. 5A-5D). Each value represents the mean ± standard deviation for each group; #P<0.05, ##P<0.01, ###P<0.005, ####P<0.0001; groups treated with Compound 1A and Compound 1B in FIGS. 4A-5D versus untreated M2 group by Dunnett's multiple comparison test. FIG. 5D shows representative graphical data of various marker levels measured in M2 macrophages that were incubated with various concentrations of exemplary free or targeted TLR7 agonists for 2 hours (FIGS. 4A-4E) or 46 hours (FIGS. 5A-5D). Each value represents the mean ± standard deviation for each group; #P<0.05, ##P<0.01, ###P<0.005, ####P<0.0001; groups treated with Compound 1A and Compound 1B in FIGS. 4A-5D versus untreated M2 group by Dunnett's multiple comparison test.

[00080] FIG. 6A shows representative graphical data of various marker levels measured in exemplary M2 macrophages treated with various concentrations of free and targeted TLR7 agonists for: (i) 48 hours (FIGS. 6A and 6B); or (ii) 2 hours, then displaced with fresh medium and cultured for the remaining 46 hours (FIGS. 6C and 6D). Each value represents the mean ± SD for each group; #P<0.05, ##P<0.01, ###P<0.005, ####P<0.0001; groups treated with Compound 1A and the Compound 1B versus the untreated group with M2, as measured by Dunnett's multiple comparison test. Petition 870250096077, dated 10 / 21 / 2025, p. 45 / 378 41 / 297 Figure 6B shows representative graphical data of various marker levels measured in M2 macrophages treated with various concentrations of free and targeted TLR7 agonists for: (i) 48 hours (Figs. 6A and 6B); or (ii) 2 hours, then displaced with fresh medium and cultured for the remaining 46 hours (Figs. 6C and 6D). Each value represents the mean ± SD for each group; #P<0.05, ##P<0.01, # ##P<0.005, ####P<0.0001; groups treated with Compound 1A and the Compound 1B versus the untreated group with M2, as measured by Dunnett's multiple comparison test. Figure 6C shows representative graphical data of various marker levels measured in M2 macrophages treated with various concentrations of free and targeted TLR7 agonists for: (i) 48 hours (Figs. 6A and 6B); or (ii) 2 hours, then displaced with fresh medium and cultured for the remaining 46 hours (Figs. 6C and 6D). Each value represents the mean ± SD for each group; #P<0.05, ##P<0.01, # ##P<0.005, ####P<0.0001; groups treated with Compound 1A and the Compound 1B versus the untreated group with M2, as measured by Dunnett's multiple comparison test. FIG. 6D shows representative graphical data of various marker levels measured in M2 macrophages treated with various concentrations of free and targeted TLR7 agonists for: (i) 48 hours (FIGS. 6A and 6B); or (ii) 2 hours, then displaced with fresh medium and cultured for the remaining 46 hours (FIGS. 6C and 6D). Each value represents the mean ± SD for each group; #P<0.05, ##P<0.01, # ##P<0.005, ####P<0.0001; groups treated with Compound 1A and the Compound 1B versus the untreated group with M2, as measured by Dunnett's multiple comparison test. Petition 870250096077, dated 10 / 21 / 2025, p. 46 / 378 42 / 297

[00081] FIG. 6E shows flow cytometry data that confirm that macrophages induced by THP-1 (a human monocytic cell line derived from a patient with acute monocytic leukemia) were positive for folate receptor beta (FR3) (FRβ+).

[00082] FIG. 6F shows exemplary TLR7-targeted agonists that are stable.

[00083] FIG. 7A shows stained images of lungs removed from mice with experimental fibrosis induced by bleomycin (BM) and stained with anti-mouse FRβ antibody, with hematoxylin-eosin (H&E) staining performed on days 7, 14 and 21 after BM-induced lung injury.

[00084] FIG. 7B shows the quantification of KKβ staining in the panels of FIG. 7A.

[00085] FIG. 7C shows the immunohistochemical (IHC) staining of EKβ from lung tissue with human idiopathic pulmonary fibrosis (IPF) (FIG. 7C) and healthy human lung tissue (FIG. 7D). FIG. 7D shows the immunohistochemical (IHC) staining of EKβ from lung tissue with human idiopathic pulmonary fibrosis (IPF) (FIG. 7C) and healthy human lung tissue (FIG. 7D).

[00086] FIG. 7E shows images of mouse tissues / organs taken from mice with or without experimental fibrosis induced by BM (control with phosphate-buffered saline (PBS)) and photographed with a fluorescent dye targeting the folate receptor.

[00087] FIG. 7F shows a fluorescence-activated cell sorting (FACS) analysis of mice with experimental fibrosis induced by BM. Petition 870250096077, dated 10 / 21 / 2025, page 47 / 378 43 / 297

[00088] FIG. 8A illustrates the treatment plan with agonists of TLR7s free and targeted in a BM model.

[00089] FIG. 8B shows the levels of pro-fibrotic (FIGS. 8B-8D) and pro-inflammatory (FIGS. 8E-8G) markers measured in mice treated with the BM model of FIG. 8A. FIG. 8C shows the levels of pro-fibrotic (FIGS. 8B-8D) and pro-inflammatory (FIGS. 8E-8G) markers measured in mice treated with the BM model of FIG. 8A. FIG. 8D shows the levels of pro-fibrotic (FIGS. 8B-8D) and pro-inflammatory (FIGS. 8E-8G) markers measured in mice treated with the BM model of FIG. 8A. FIG. 8E shows the levels of pro-fibrotic (FIGS. 8B-8D) and pro-inflammatory (FIGS. 8E-8G) markers measured in mice treated with the BM model of FIG. 8A. FIG. 8F shows the levels of pro-fibrotic (FIGS. 8B-8D) and pro-inflammatory (FIGS. 8E-8G) markers measured in mice treated with the BM model of FIG. 8A. FIG. 8G shows the levels of pro-fibrotic (FIGS. 8B-8D) and pro-inflammatory (FIGS. 8E-8G) markers measured in mice treated with the BM model of FIG. 8A.

[00090] FIG. 8H shows the number of cells in the bronchoalveolar lavage fluid (BAL) of mice treated with the BM model of FIG. 8A.

[00091] FIG. 9A shows survival curves (FIG. 9A) and changes in body weight (FIG. 9B) of mice with pulmonary fibrosis treated Petition 870250096077, dated 10 / 21 / 2025, page 48 / 378 44 / 297 with targeted and non-targeted TLR7 drugs. FIG. 9B shows survival curves (FIG. 9A) and changes in body weight (FIG. 9B) of mice with pulmonary fibrosis treated with targeted and non-targeted TLR7 drugs.

[00092] FIG. 10A shows the hydroxyproline content (μg / lung) of lung tissue as a measure of fibrosis.

[00093] FIG. 10B shows lung tissue in FIG. 9A with H&E staining (FIG. 10B) and Masson's trichrome staining (collagen) (FIG. 10C). FIG. 10C shows lung tissue in FIG. 9A with H&E staining (FIG. 10B) and Masson's trichrome staining (collagen) (FIG. 10C).

[00094] FIG. 11A shows illustrative survival curves (FIG. 11A) and body weight change curves (FIG. 11B) of mice with pulmonary fibrosis treated with targeted TLR7 agonists, with each value representing the mean ± standard deviation for each group. FIG. 11B shows illustrative survival curves (FIG. 11A) and body weight change curves (FIG. 11B) of mice with pulmonary fibrosis treated with targeted TLR7 agonists, with each value representing the mean ± standard deviation for each group.

[00095] FIG. 12 shows the dose-dependent effect of an agonist Figure 12A shows graphical data related to the body weight of BM-induced mice over time. Figure 12B shows the measurement of hydroxyproline content in lung tissue treated with various doses of the exemplary compound provided here (e.g., Compound 1B). Figure 12C shows images. Petition 870250096077, dated 10 / 21 / 2025, page 49 / 378 45 / 297 for histological analysis of lung tissue with various stains. Each value represents the mean ± SD for each group; *P<0.05, **P<0.005, ***<0.0005; saline group versus vehicle group, treated groups versus vehicle group by Student's t-test.

[00096] FIG. 13A shows various levels of markers measured in M2-type macrophages reprogrammed according to the methods described herein with various concentrations of an exemplary targeted TLR7 agonist for 48 hours, and each value represents the mean ± SD for each group. FIG. 13B shows various marker levels measured in M2-type macrophages reprogrammed according to the methods described herein with various concentrations of an exemplary targeted TLR7 agonist for 48 hours, and each value represents the mean ± SD for each group. FIG. 13C shows various marker levels measured in M2-type macrophages reprogrammed according to the methods described herein with various concentrations of an exemplary targeted TLR7 agonist for 48 hours, and each value represents the mean ± SD for each group. FIG. 13D shows various marker levels measured in M2-type macrophages reprogrammed according to the methods described herein with various concentrations of an exemplary targeted TLR7 agonist for 48 hours, and each value represents the mean ± SD for each group.

[00097] FIG. 14A shows various levels of markers measured in M2-type macrophages reprogrammed according to the methods here Petition 870250096077, dated 10 / 21 / 2025, p. 50 / 378 Figure 46 / 297 is described with various concentrations of exemplary free and targeted TLR7 agonists. FIG. 14A shows CCL18, FIG. 14B shows CD206, and FIG. 14C shows IL-1β. Each value shown in FIGS. 14A-14C represents the mean ± SD for each group; #P<0.05, ##P<0.005, ###P<0.0005; ####P<0.0001; Groups treated with Compound 3A, the Compound 3B and Compound 3C versus the untreated group with M2 by Dunnett's multiple comparison test. Figure 14B shows various marker levels measured in M2-type macrophages reprogrammed according to the methods described herein with various concentrations of exemplary free and targeted TLR7 agonists. Figure 14A shows CCL18, Figure 14B shows CD206, and Figure 14C shows IL-1β. Each value shown in Figures 14A-14C represents the mean ± SD for each group; #P<0.05, ##P<0.005, ###P<0.0005; ####P<0.0001; Groups treated with Compound 3A, the Compound 3B and Compound 3C versus the untreated group with M2 by Dunnett's multiple comparison test. Figure 14C shows various marker levels measured in M2-type macrophages reprogrammed according to the methods described herein with various concentrations of exemplary free and targeted TLR7 agonists. Figure 14A shows CCL18, Figure 14B shows CD206, and Figure 14C shows IL-1β. Each value shown in Figures 14A-14C represents the mean ± SD for each group; #P<0.05, ##P<0.005, ###P<0.0005; ####P<0.0001; Groups treated with Compound 3A, the Compound 3B and Compound 3C versus the untreated group with M2 by Dunnett's multiple comparison test.

[00098] FIG. 15 shows the levels of secreted chemokine ligand 18 (CCL18) protein (CC motif) in each cell group of FIGS. Petition 870250096077, dated 10 / 21 / 2025, p. 51 / 378 47 / 297 14A-14C after treatment with exemplary free and targeted TLR7 agonists.

[00099] FIG. 16 illustrates a methodology for a murine model of BM. [000100] FIG. 17A shows the purity of an exemplary targeted TLR7 agonist. FIG. 17B shows the purity of an exemplary targeted TLR7 agonist. [000101] FIG. 18A shows data from the in vivo study of FIG. 16, including survival curves (FIG. 18A), changes in body weight (FIG. 18B and 18D), concentration of cells with BALF present (FIG. 18C), hydroxyproline concentration (μg HP / lobe) in live mice (FIG. 18E) and in all mice (i.e., including live mice and those that died before day 21) (FIG. 18F). FIG. 18B shows data from the in vivo study of FIG. 16, including survival curves (FIG. 18A), changes in body weight (FIG. 18B and 18D), concentration of cells with BALF present (FIG. 18C), hydroxyproline concentration (μg HP / lobe) in live mice (FIG. 18E) and in all mice (i.e., including live mice and those that died before day 21) (FIG. 18F). FIG. 18C shows data from the in vivo study of FIG. 16, including survival curves (FIG. 18A), changes in body weight (FIG. 18B and 18D), concentration of cells with BALF present (FIG. 18C), hydroxyproline concentration (μg HP / lobe) in live mice (FIG. 18E) and in all mice (i.e., including live mice and those that died before day 21) (FIG. 18F). Petition 870250096077, dated 10 / 21 / 2025, page 52 / 378 48 / 297 FIG. 18D shows data from the in vivo study of FIG. 16, including survival curves (FIG. 18A), changes in body weight (FIG. 18B and 18D), concentration of cells with BALF present (FIG. 18C), hydroxyproline concentration (μg HP / lobe) in live mice (FIG. 18E) and in all mice (i.e., including live mice and those that died before day 21) (FIG. 18F). FIG. 18E shows data from the in vivo study of FIG. 16, including survival curves (FIG. 18A), changes in body weight (FIG. 18B and 18D), concentration of cells with BALF present (FIG. 18C), hydroxyproline concentration (μg HP / lobe) in live mice (FIG. 18E) and in all mice (i.e., including live mice and those that died before day 21) (FIG. 18F). FIG. 18F shows data from the in vivo study of FIG. 16, including survival curves (FIG. 18A), changes in body weight (FIG. 18B and 18D), concentration of cells with BALF present (FIG. 18C), hydroxyproline concentration (μg HP / lobe) in live mice (FIG. 18E) and in all mice (i.e., including live mice and those that died before day 21) (FIG. 18F). [000102] FIG. 19A shows that targeted and untargeted TLR7 agonists reprogram anti-inflammatory macrophages derived from human monocytes to an antifibrotic phenotype, with FIG. 19A showing Arg1, FIG. 19B showing CD206, FIG. 19C showing CD163, FIG. 19D showing CCL18, FIG. 19E showing CXCL10 and FIG. 19F showing IL-6. Mean ± SD. Statistical significance between groups was determined using the unpaired two-tailed t-test (*P<0.05, **P<0.01, ***P<0.001, ****P<0.0001). Petition 870250096077, dated 10 / 21 / 2025, page 53 / 378 49 / 297 FIG. 19B shows that targeted and untargeted TLR7 agonists reprogram anti-inflammatory macrophages derived from human monocytes to an antifibrotic phenotype, with FIG. 19A showing Arg1, FIG. 19B showing CD206, FIG. 19C showing CD163, FIG. 19D showing CCL18, FIG. 19E showing CXCL10, and FIG. 19F showing IL-6. Mean ± SD. Statistical significance between groups was determined using the unpaired two-tailed t-test (*P<0.05, **P<0.01, ***P<0.001, ****P<0.0001). FIG. 19C shows that targeted and untargeted TLR7 agonists reprogram anti-inflammatory macrophages derived from human monocytes to an antifibrotic phenotype, with FIG. 19A showing Arg1, FIG. 19B showing CD206, FIG. 19C showing CD163, FIG. 19D showing CCL18, FIG. 19E showing CXCL10, and FIG. 19F showing IL-6. Mean ± SD. Statistical significance between groups was determined using the unpaired two-tailed t-test (*P<0.05, **P<0.01, ***P<0.001, ****P<0.0001). FIG. 19D shows that targeted and untargeted TLR7 agonists reprogram anti-inflammatory macrophages derived from human monocytes to an antifibrotic phenotype, with FIG. 19A showing Arg1, FIG. 19B showing CD206, FIG. 19C showing CD163, FIG. 19D showing CCL18, FIG. 19E showing CXCL10, and FIG. 19F showing IL-6. Mean ± SD. Statistical significance between groups was determined using the unpaired two-tailed t-test (*P<0.05, **P<0.01, ***P<0.001, ****P<0.0001). FIG. 19E shows that targeted and untargeted TLR7 agonists reprogram anti-inflammatory macrophages derived from human monocytes to an antifibrotic phenotype, with FIG. 19A Petition 870250096077, dated 10 / 21 / 2025, page 54 / 378 Figure 19A shows Arg1, Figure 19B shows CD206, Figure 19C shows CD163, Figure 19D shows CCL18, Figure 19E shows CXCL10, and Figure 19F shows IL-6. Mean ± SD. Statistical significance between groups was determined using the unpaired two-tailed t-test (*P<0.05, **P<0.01, ***P<0.001, ****P<0.0001). FIG. 19F shows that targeted and untargeted TLR7 agonists reprogram anti-inflammatory macrophages derived from human monocytes to an antifibrotic phenotype, with FIG. 19A showing Arg1, FIG. 19B showing CD206, FIG. 19C showing CD163, FIG. 19D showing CCL18, FIG. 19E showing CXCL10, and FIG. 19F showing IL-6. Mean ± SD. Statistical significance between groups was determined using the unpaired two-tailed t-test (*P<0.05, **P<0.01, ***P<0.001, ****P<0.0001). [000103] FIG. 20 shows a comparison of plasma cytokine levels in healthy mice after treatment with Compound 1A versus Compound 1B (FIGS. 20A-20F), with FIGS. 20A and 20D showing IL-6, FIGS. 20B and 20E showing IFNα, and FIGS. 20C and 20F showing tumor necrosis factor α (TNF-α). FIG. 20G shows the change in body weight after treatment of mice with exemplary compounds, with change in body weight as a measure of systemic toxicity during alternate-day administration (n = 2); mean ± SD. Statistical significance between groups was compared using the unpaired two-tailed t-test (*P<0.05, **P<0.01, ***P<0.001). [000104] FIG. 21 shows healthy and fibrotic lungs described in FIG. 6 stained with 4',6-diamidino-2-phenylindole (DAPI) (nuclei; blue), anti-F4 / 80 (macrophages; red) and anti-mannose receptor (CD206). [000105] FIG. 22 shows the effect of several exemplary compounds on the expression of interleukin 6 (IL-6) in blood mononuclear cells. Petition 870250096077, dated 10 / 21 / 2025, p. 55 / 378 51 / 297 peripheral. [000106] FIG. 23A shows the in vitro effects of several exemplary compounds on the induction of IL-6 and CXC motif chemokine 10 (CXCL-10) in monocyte-derived M2- macrophages for 48 hours. FIG. 23B shows the in vitro effects of several exemplary compounds on the induction of IL-6 and CXC motif chemokine 10 (CXCL-10) in monocyte-derived M2-macrophages for 48 hours. [000107] FIG. 23C shows the in vivo effects of several exemplary compounds on the production of IL-6 and tumor necrosis factor α (TNFa). FIG. 23D shows the in vivo effects of several exemplary compounds on the production of IL-6 and tumor necrosis factor α (TNFα). [000108] FIG. 24A shows data from in vivo combination studies of the non-releasable conjugate FA-TLR7-1A (Compound 1000) (3 nmol / mouse) with anti-CTLA-4 (10 mg / kg, twice weekly) in a 4T1 orthotopic solid tumor model, with FIG. 24A showing tumor volume measured on alternate days after treatment; FIG. 24B showing a graph of tumor weight measured at the end of the study; FIG. 24C showing graphs of tumor volumes in individual mice in the different treatment groups; FIG. 24D showing a graph of tumor volume after treatment with FA-TLR7-1A, PD-1 and the FA-TLR7-1A + PD-1 combination; FIG. Figure 24E shows graphs of tumor volume in individual mice after treatment with PD-1 or a combination of FA-TLR7-1A + PD-1; and Figure 24F shows a graph of tumor volume versus days after the start of treatment. Petition 870250096077, dated 10 / 21 / 2025, page 56 / 378 52 / 297 FIG. 24B shows data from in vivo combination studies of the non-releasable conjugate FA-TLR7-1A (Compound 1000) (3 nmol / mouse) with anti-CTLA-4 (10 mg / kg, twice weekly) in a 4T1 orthotopic solid tumor model, with FIG. 24A showing tumor volume measured on alternate days after treatment; FIG. 24B showing a graph of tumor weight measured at the end of the study; FIG. 24C showing graphs of tumor volumes in individual mice in the different treatment groups; FIG. 24D showing a graph of tumor volume after treatment with FA-TLR7-1A, PD-1 and the FA-TLR7-1A + PD-1 combination; FIG. 24E showing graphs of tumor volume of individual mice after treatment with PD-1 or a combination of FA-TLR7-1A + PD-1; and FIG. Figure 24F shows a graph of tumor volume versus days after the start of treatment. FIG. 24C shows data from in vivo combination studies of the non-releasable conjugate FA-TLR7-1A (Compound 1000) (3 nmol / mouse) with anti-CTLA-4 (10 mg / kg, twice weekly) in a 4T1 orthotopic solid tumor model, with FIG. 24A showing tumor volume measured on alternate days after treatment; FIG. 24B showing a graph of tumor weight measured at the end of the study; FIG. 24C showing graphs of tumor volumes in individual mice in the different treatment groups; FIG. 24D showing a graph of tumor volume after treatment with FA-TLR7-1A, PD-1 and the FA-TLR7-1A + PD-1 combination; FIG. 24E showing graphs of tumor volume of individual mice after treatment with PD-1 or a combination of FA-TLR7-1A + PD-1; and FIG. Figure 24F shows a graph of tumor volume versus days after the start of treatment. FIG. 24D shows data from in vivo combination studies of the non-releasable conjugate FA-TLR7-1A (Compound 1000) (3 Petition 870250096077, dated 10 / 21 / 2025, page 57 / 378 53 / 297 nmol / mouse) with anti-CTLA-4 (10 mg / kg, twice weekly) in a 4T1 orthotopic solid tumor model, with FIG. 24A showing tumor volume measured on alternate days after treatment; FIG. 24B showing a graph of tumor weight measured at the end of the study; FIG. 24C showing graphs of tumor volumes in individual mice in the different treatment groups; FIG. 24D showing a graph of tumor volume after treatment with FA-TLR7-1A, PD-1 and the combination FA-TLR7-1A + PD-1; FIG. 24E showing graphs of tumor volume of individual mice after treatment with PD-1 or a combination of FA-TLR7-1A + PD-1; and FIG. 24F showing a graph of tumor volume versus days after the start of treatment. FIG. 24E shows data from in vivo combination studies of the non-releasable conjugate FA-TLR7-1A (Compound 1000) (3 nmol / mouse) with anti-CTLA-4 (10 mg / kg, twice weekly) in a 4T1 orthotopic solid tumor model, with FIG. 24A showing tumor volume measured on alternate days after treatment; FIG. 24B showing a graph of tumor weight measured at the end of the study; FIG. 24C showing graphs of tumor volumes in individual mice in the different treatment groups; FIG. 24D showing a graph of tumor volume after treatment with FA-TLR7-1A, PD-1 and the FA-TLR7-1A + PD-1 combination; FIG. 24E showing graphs of tumor volume of individual mice after treatment with PD-1 or a combination of FA-TLR7-1A + PD-1; and FIG. Figure 24F shows a graph of tumor volume versus days after the start of treatment. FIG. 24F shows data from in vivo combination studies of the non-releasable conjugate FA-TLR7-1A (Compound 1000) (3 nmol / mouse) with anti-CTLA-4 (10 mg / kg, twice weekly) in a 4T1 orthotopic solid tumor model, with FIG. 24A showing Petition 870250096077, dated 10 / 21 / 2025, page 58 / 378 Figure 24A shows a graph of tumor volume measured on alternate days after treatment; Figure 24B shows a graph of tumor weight measured at the end of the study; Figure 24C shows graphs of tumor volumes in individual mice in the different treatment groups; Figure 24D shows a graph of tumor volume after treatment with FA-TLR7-1A, PD-1, and the combination of FA-TLR7-1A + PD-1; Figure 24E shows graphs of tumor volume in individual mice after treatment with PD-1 or a combination of FA-TLR7-1A + PD-1; and Figure 24F shows a graph of tumor volume versus days after the start of treatment. [000109] FIG. 25 shows graphs of the results of immune cell analysis of digested tumor tissues after combined in vivo treatment of slow-release conjugate FA-TLR7-1A (3 nmol / mouse) with anti-CTLA-4 (10 mg / kg, twice a week) in the 4T1 orthotopic solid tumor model. [000110] FIG. 26 shows IHC images of 4T1 tumor tissues after treatment with FA-TLR7-1A (Compound 1000), which were stained with DAPI (white circle with solid line) and antibodies to Arg-1 (white arrow, top line), iNOS (white circle with dashed line) and CD8 (white arrow, bottom line). [000111] FIG. 27 is a summary of an in vivo combined therapy methodology comprising treatment with FA-TLR7-1A with anti-PD-1 / anti-PD-L1 antibodies in a 4T1 tumor model. [000112] FIG. 28 shows a graph of the tumor volume from the in vivo combination study of FIG. 27, measured after treatment with an FA-TLR7-1A conjugate (Compound 1000) (3 nmol / mouse) in combination with anti-PD-1 (5 mg / kg, twice weekly) in an MC38 solid tumor model. [000113] FIG. 29A shows immune cell analysis data from Petition 870250096077, dated 10 / 21 / 2025, page 59 / 378 55 / 297 MC38 tumor samples digested after treatment, as described in FIG. 27. [000114] FIG. 29B shows the tumor volume measured after mice cured from the combination study described in FIG. 28 and healthy control mice were again challenged with 0.5 million MC38 cells. [000115] FIG. 30 is a summary of an in vivo combination therapy methodology comprising treatment with a non-releasable FA-TLR7-1A conjugate (Compound 1000) with anti-CTLA-4 antibodies in a Lewis LL / 2 lung carcinoma tumor model. [000116] FIG. 31 shows a graph of tumor volume from the in vivo combination study of FIG. 30, measured on alternate days after treatment with an FA-TLR7-1A conjugate (Compound 1000) (3 nmol / mouse) in combination with anti-CTLA-4 (10 mg / kg, twice weekly) in a Lewis LL / 2 lung carcinoma tumor model. [000117] FIG. 32A shows a graph of the change in body weight of mice during combination therapy treatment in a 4T1 tumor model from Example 16. [000118] FIG. 32B shows a graph of the change in body weight of mice during the combined therapy treatment of Example 17. [000119] FIG. 32C shows a graph of the change in body weight of mice as a measure of systemic toxicity after chronic administration of a dose of 60 nmoles / mice / day of TLR7-1A (Compound 1) or FA-TLR7-1A (Compound 1000) to healthy mice. [000120] Although the present disclosure is subject to various modifications and alternative forms, its exemplary forms are Petition 870250096077, dated 10 / 21 / 2025, page 60 / 378 56 / 297 shown as examples in the drawings and described in detail herein. DETAILED DESCRIPTION [000121] The compounds, combinations, compositions, and methods of the present disclosure generally target an individual's innate immune system and reprogram the polarization of an M2-type macrophage to the M1-type in favor of the pro-inflammatory properties of the M1-type phenotype. For example, in at least one exemplary embodiment, such compounds and compositions comprise a targeting fraction to target the folate receptor β (FRe), such as a folate receptor-binding ligand, or an analog, functional fragment, derivative, or radical thereof (e.g., a pteroyl amino acid), coupled or linked to an immune modulator or a pharmaceutically acceptable salt thereof. The term "ligand" is a molecule, ion, or atom that is linked to the central atom or ion (e.g., a drug) of a compound. [000122] As described in detail below, such modalities can utilize the limited expression of FRβ to target the systemically administered compound directly to FRβ-expressing cells (e.g., those of cancerous tissue), so that the immunomodulatory component can then convert—for example, reprogram—activated myeloid cells (e.g., M2-type macrophages) into a pro-inflammatory M1 polarization. This targeting design can advantageously prevent systemic activation of the immune system (i.e., reduce systemic exposure to such a compound) and thus avoid toxicity. [000123] Other illustrative embodiments may include a ligand disposed between the targeting fraction and the immunomodulator. Petition 870250096077, dated 10 / 21 / 2025, page 61 / 378 57 / 297 These ligands can be releasable or non-releasable. A compound / composition comprising a releasable ligand may, when administered, result in the release of the targeting fraction and the immunomodulator from each other at the time the immunomodulator becomes active or near it. Additionally or alternatively, in embodiments where a compound comprises a non-releasable ligand, when administered, the targeting fraction and the immunomodulator are not rapidly released under physiological conditions. Thus, the components of the compound remain together after uptake by a target cell and / or activation of the immunomodulator. [000124] Several modalities will be described below, as well as data related to examples that support them. [000125] Compounds [000126] The compound may comprise a drug (e.g., a radical thereof) (e.g., an immunomodulator) or a pharmaceutically acceptable salt or hydrate thereof conjugated with a targeting moiety (e.g., a radical thereof). The immunomodulator (e.g., a radical thereof) may be conjugated directly to the targeting moiety (e.g., a radical thereof) or via a ligand (e.g., optionally comprising a spacer). [000127] FIG. 1A shows at least one embodiment of compound 100. Here, compound 100 comprises an immune modulator 102 (or drug or radical thereof), for example, having Formula I, where R3 is a hydroxyl group. The immune modulator 102 (e.g., a radical thereof) can be conjugated to a targeting moiety 104 (e.g., a radical thereof) via a ligand 106. Here, the targeting moiety 104 (e.g., a radical thereof) is a folate and the ligand (e.g., non-releasable) 106 is a Petition 870250096077, dated 10 / 21 / 2025, p. 62 / 378 58 / 297 polyethylene glycol (PEG) binder repeated n times, where n is an integer between 1 and 32. [000128] In certain forms, the compound 100 can be represented by the formula: QLT, where Q is a radical of a folate receptor-binding ligand / targeting fraction 104, L is a ligand 106, and T is a radical of a TLR agonist / immunomodulator 102. The L ligand may comprise any of the ligand formulas presented here. [000129] Similarly, FIG. 1B shows at least one embodiment of compound 150. Compound 150 has an immune modulator / drug 152 (e.g., a radical thereof) that is a Toll-like receptor 7 agonist (e.g., a radical thereof), for example, having Formula III, conjugated to a targeting moiety 154 (e.g., a radical thereof) via a ligand 156 (e.g., releasable). [000130] Immune Modulators [000131] “Immune modulator” means any drug, warhead or other composition or compound that stimulates or otherwise affects an individual’s immune system by inducing activation or enhancing the activity of one or more components of the immune system. For example, and without limitation, immune modulators may include a compound or composition that targets one or more pattern recognition receptors or damage-associated molecular patterns (DAMPs), in addition to, or instead of, targeting signaling pathways in immune cells. “Pattern recognition receptors” means and includes any immune receptors that are expressed on the membranes of leukocytes – for example, at least macrophages – and Petition 870250096077, dated 10 / 21 / 2025, page 63 / 378 59 / 297 can bind to specific ligands that activate the receptor and ultimately lead to an innate immune response (and, in certain cases, eventually to the development of specific acquired immunity to the antigen). The immune modulator (e.g., or radical of an immune modulator) may comprise a pharmaceutically acceptable salt or hydrate thereof. [000132] Exemplary examples of immunomodulators may include, without limitation, TLR agonists, interferon gene stimulators (STINGs), nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), retinoic acid-inducible gene-like receptors (RIG-I) (RLRs), melanoma-like receptors 2 (AIM2)-absent (ALRs), the receptor for advanced glycation end products (RAGE), or any other pattern recognition receptor located in the endosome or cytoplasm of a cell. Immunological modulators may additionally or alternatively comprise a nuclear factor kappa light chain activator of activated B cell nuclear factor (NFk3) or an Iκβ kinase inhibitor, which act further downstream in the pathway. Table 1 provides examples of such NF-κB activators or IκB kinase inhibitors that can be used as immunomodulators. [000133] Table 1. Activators / Inductors of Nκβ Structured Compound Petition 870250096077, dated 10 / 21 / 2025, page 64 / 378 60 / 297 Petition 870250096077, dated 10 / 21 / 2025, page 65 / 378 61 / 297 [000134] “TLRs” are a class of proteins that play a role in the innate immune system and are an example of pattern recognition receptors. TLRs can be single receptors that span the membrane and recognize structurally conserved molecules derived from microbes. TLRs can be expressed on the membranes of leukocytes, including, for example, dendritic cells, macrophages, natural killer cells, cells of adaptive immunity (e.g., T and B lymphocytes), and non-immune cells (epithelial and endothelial cells and fibroblasts). Non-limiting examples of TLRs include Petition 870250096077, dated 10 / 21 / 2025, page 66 / 378 62 / 297 TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13. In some embodiments, a TLR agonist provided here binds to one or more TLRs. In some embodiments, a TLR agonist provided here binds to TLR7, TLR8, or TLR9. In some embodiments, a TLR agonist provided here binds to TLR7. In some embodiments, a TLR agonist provided here binds to both TLR7 and TLR8 (a TLR 7 / 8 agonist). In some embodiments, an agonist is a ligand that binds to and activates a receptor. [000135] In some cases, such as when the compound is a (e.g., potent) TLR-7 / 8 agonist, the immunomodulator (or its radical) may be highly toxic if administered systemically in an unconjugated form. In some cases, it is desirable to reduce and / or eliminate the systemic toxicity associated with such compounds. In some cases, a radical of a compound has reduced toxicity relative to the free form of such compound (e.g., reduced by 10%-15%, 15%-20%, 20%-30%, 30%-40%, 40%-50%, 50%-60%, 60%-70%, 70%-75%, 75%-80%, 80%-9%, 90% or 90%-99% (all ranges listed, including stated endpoints and all 1% increments covered therein)).Furthermore, in some cases, conjugated forms of the compounds are effective at comparable or lower concentrations (for example, having a median effective dose concentration (ED50) of 120% or less of the free form, 100% or less, 80% or less, 60% or less, or 40% or less) compared to a free form of the immunomodulator. [000136] The immunomodulator, or its pharmaceutically acceptable salt or hydrate, may comprise any therapeutic agent (e.g., drug) suitable for reprogramming activated macrophages (M2-like phenotype) to an M1-like phenotype. In certain embodiments, the immunomodulator operates in the endosome and / or cytoplasm of the cell (e.g., depending on its structure). In at least one Petition 870250096077, dated 10 / 21 / 2025, page 67 / 378 63 / 297 embodiment, the immune modulator is one that positively controls a pattern recognition receptor and / or its downstream signaling pathways (in each case, part of the innate immune system), such as, for example, TLR, NLR, RLR, ALR, RAGE and / or STING agonists and / or a kinase from the Pelle receptor / interleukin-1 (IRAK)-associated kinase family, such as an IRAK-M inhibitor. In other embodiments, the compound comprises a phosphoinositide 3-kinase (PI3K) inhibitor or other inhibitor that negatively controls the adaptive immune system (for example, which may be employed alone or in conjunction with an immune modulator that targets a pattern recognition receptor or a DAMP).In some embodiments, especially when used in cancer treatment, the compound (or its pharmaceutically acceptable salt or hydrate) comprises a combination of (a) a radical of an immunomodulator that targets a pattern recognition receptor or a DAMP and / or is an agonist of downstream signaling pathways of the subject's innate immune system, and (b) an inhibitor of mammalian target of rapamycin (mTOR) (competitive with ATP or not), such as, for example, rapamycin or CZ415. [000137] In some embodiments, the immunomodulator of the compound (or its pharmaceutically acceptable salt or hydrate) comprises a TLR agonist (e.g., a radical thereof), for example, and without limitation, a TLR3 agonist, a TLR7 agonist, a TLR7 / 8 agonist, a TLR8 agonist, or a TLR9 agonist (e.g., all of which bind to a TLR present in the endosome of a cell). For example, and without limitation, in at least one exemplary embodiment, the immunomodulator of the compound (or its pharmaceutically acceptable salt or hydrate) may be selected from among the compounds listed in Table 2 below (and, for example, comprise a radical thereof). Petition 870250096077, dated 10 / 21 / 2025, p. 68 / 378 64 / 297 [000138] Table 2. TLR agonists. Compound Structure / Description Type A nh2 u TLR7 Agonist B nh2 *03 Ql V / TLR7 Agonist C NHa nAL-n / ji 1 7— Q] Nc o Kl 4 0 TLR7 Agonist D NHa nAL-n / j 1 7— Qj V o Kl 4 0 A TLR7 Agonist EX Zx Zx § zz QX / « Z \ ZZ=^ zx TLR7 agonist Petition 870250096077, of 21 / 10 / 2025, p. 69 / 378 65 / 297 F nh2 II A / — U TLR7 Agonist G o hn 'TT'Nvà HSN ^OH0 ] ^OH HO^ TLR7 Agonist H Br. 0 Là 6Γ ^NH, H 1 Agonist TLR7 I ÍVZ \=AVi oz í Agonist TLR7 J nh2 1 H JI À. / 0 AH V___ / ^N \ TLR7 agonist Petition 870250096077, of 21 / 10 / 2025, p. 70 / 378 66 / 297 κ ) V À # Z Λ ff w rr X o 0,^ TLR7 Agonist L o^°H ? °xNl >o HN N-\ \__# X__ / OH TLR7 Agonist Μ NH, 1 H o TLR7 Agonist N .'X ZX o TLR7 Agonist Ο 4 / / z \_ / I / ----( w TLR7 / 8 Agonist Petition 870250096077, of 21 / 10 / 2025, p. 71 / 378 67 / 297 PO Js o->° 1 TLR7 / 8 Agonist Q See, for example, Lipanov et al., “The structure of poly(dA):poly(dT) in a condensed state and in solution”, Nucleic Acids Research 15 (14): 5833-5844 (1987). TLR7 / 8 Agonist RN NH2 TLR8 Agonist S Vo X / -1 TLR8 Agonist T fN 1 X w 2=0 TLR8 Agonist Petition 870250096077, dated 10 / 21 / 2025, p. 72 / 378 68 / 297 U Short single-stranded synthetic DNA molecules containing unmethylated CpG dinucleotides in specific sequence contexts (CpG motifs) (CpG ODN) TLR9 agonist V Synthetic oligonucleotide containing unmethylated CpG dinucleotides with potential immunopotentiating activity (IMO 2005) TLR9 agonist W Short, synthetic, unmethylated CpG oligonucleotide (CpG ODN) with immunostimulatory activity (1018ISS) TLR9 agonist X Comprises an inosine poly(I) homopolymer strand annealed to a cytidine strand (poly(I:C)) TLR3 agonist Y Poly(C) homopolymer TLR3 agonist Petition 870250096077, dated 10 / 21 / 2025, p. 73 / 378 69 / 297 [000139] In some embodiments, the immune modulator comprises a TLR7 agonist or a radical thereof. In some embodiments, an immune modulator (or radical) (e.g., TLR7 agonist) has a Formula I structure: (I) or is a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, RI is an amine. In some embodiments, R2 is a bond (e.g., single) or an amine (e.g., -NH-). In certain embodiments, R3 is an H, an alkyl, a hydroxyl group, or any other suitable substituent (e.g., as described herein). In some embodiments, X is CH2, NH, O, or S. In some embodiments, where a compound comprises a radical of Formula I, a directing moiety is conjugated or connected to it in Petition 870250096077, dated 10 / 21 / 2025, p. 74 / 378 70 / 297 any suitable location, such as in or through RI, R2 and / or R3 (e.g., through a binder and / or directly). [000140] In at least one exemplary embodiment, a compound is or comprises an immune modulator (or radical thereof) (e.g., TLR7 agonist) of Formula Ia: or is a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, X is a CH or an N. In some embodiments, RI is -NH2 or -NH-R1X. In some embodiments, R2 is H, alkyl, alkenyl, alkynyl, alicyclic, aryl, biaryl, heteroaryl, -NH-R2X, -O-R2X, -S-R2X, or In specific embodiments, each of RIX, R2X, and R2Y is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, alicyclic, aryl, biaryl, and heteroaryl. In some embodiments, it is a non-aromatic mono- or bicyclic heterocycle containing N members from 3 to 10. In some embodiments, where a compound comprises a radical of formula Ia, a fraction of Petition 870250096077, dated 10 / 21 / 2025, p. 75 / 378 71 / 297 routing is coupled or connected to it at any suitable location, such as in or through RI, R2 and / or R3 (e.g., through a ligand and / or directly). [000141] In some embodiments, a compound comprises an immune modulator having or comprising a Formula II structure: (II) or is a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, RI is an amine. In some embodiments, R2 is a (e.g., single) or -NH- bond. In some embodiments, R3 is H, alkyl, hydroxyl group, or any other substituent as described herein. In some embodiments, X is a CH2, NH, O, or S. In some embodiments where a compound comprises a radical of formula II, a targeting moiety is conjugated or connected to it at any suitable location, such as at or through RI, R2, and / or R3 (e.g., through a ligand and / or directly). [000142] In other embodiments, the immunomodulator of a compound may include or comprise a drug comprising the TLR agonist (for example, or a radical thereof) of Formula III or a pharmaceutically acceptable salt or hydrate thereof: Petition 870250096077, dated 10 / 21 / 2025, p. 76 / 378 72 / 297 (III) where RI is an amine group and R3 is a hydroxyl group. In addition, if desired, a targeting moiety (e.g., or a radical thereof) or other ligand may be conjugated to the agonist of Formula III at RI or R3 (via a ligand or directly). The TLR agonist (e.g., or a radical thereof) of Formula III is a TLR7 agonist and at least ten times (l0x) as potent as conventionally available TLR7 agonists. [000143] In certain embodiments, the immunomodulator of the compound may be or comprise a TLR7 agonist (e.g., or a radical thereof) of Formula IV or a pharmaceutically acceptable salt or hydrate thereof: (IV) where RI is an amine group and R2 is a single -NH- bond. [000144] In certain embodiments, the immune modulator comprises a TLR agonist of Formula X or XX, or is a pharmaceutically acceptable salt of Formula X or XX: Petition 870250096077, dated 10 / 21 / 2025, p. 77 / 378 73 / 297 (XX) where, in Formulas X and XX, R1 is -NH2 or -NH-R1X, R2 is an H, an alkyl, an alkenyl, an alkynyl, an alicyclic, an aryl, an ^2X —N R2Ybiaryl, a heteroaryl, -NH-R2X, -O-R2X, -S-R2X, or Q —N ) and is a non-aromatic mono- or bicyclic heterocycle containing N of 3 to 10 members, wherein, in Formula X, R3 is OH, -SH, -NH2 or -NH-R1X, wherein, in Formula XX, X is a CH or N, and each of RIX, R2X and R2Y is independently selected from the group consisting of an H, an alkyl, an alkenyl, an alkynyl, an alicyclic, an aryl, a biaryl and a heteroaryl. [000145] In certain modalities, the immunomodulatory group (by Petition 870250096077, dated 10 / 21 / 2025, p. 78 / 378 74 / 297 example, TLR7 agonist) of the compound is a radical with a structure of Formula XX and, more specifically, Formula XX': R1E (XX% where: R1B is -NH2 or -NH-R1X, R2B is a hydrogen (H), an alkyl, an alkenyl, an alkynyl, an alicyclic, an aryl, a biaryl, a heteroaryl, \—N NH-R2X, -O-R2X, -S-R2X, R2You R2Y, each of RIX, R2X, and R2Y are selected independently from the group consisting of an H, an alkyl, an alkenyl, an alkynyl, an alicyclic, an aryl, a biaryl, and a heteroaryl, and It is a non-aromatic, monocyclic or bicyclic heterocycle containing N, with 3 to 10 members, and Petition 870250096077, dated 10 / 21 / 2025, p. 79 / 378 75 / 297 X is CH or nitrogen (N). [000146] Alkyl, alkoxy, etc., each denotes a linear (i.e., unbranched) or branched chain, or a combination thereof, which may be fully saturated, mono- or polyunsaturated, and may include di- and multivalent radicals, having the designated number of carbon atoms (i.e., C1-C10 means from one to ten carbons). Examples of saturated hydrocarbon radicals include, without limitation, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, (cyclohexyl)methyl, and homologues and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-noctyl, and the like. An unsaturated alkyl group is one that has one or more double or triple bonds. Examples of unsaturated alkyl groups include, without limitation, vinyl, 2-propenyl, crotyl-2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-penadienyl), ethinyl, 1- and 3-propynyl, 3-butynyl and higher homologs and isomers.An alkoxy is an alkyl group linked to the rest of the molecule through an oxygen ligand (—O—). In some embodiments, alkoxy refers to a radical linked through an oxygen atom of the formula -O-alkyl. [000147] In general, the term “acyl” or “acyl substituent” refers to a group derived from the removal of one or more hydroxyl groups from an oxoacid, including inorganic acids, and contains a double-bonded oxygen atom and an alkyl group. Furthermore, reference to an individual radical, such as “propyl,” only covers the straight-chain radical; specifically, a branched-chain isomer, such as “isopropyl,” is referenced. [000148] In certain embodiments, the TLR7 agonist has Formula X, and the TLR7 agonist radical is conjugated to the targeting moiety at any one of R1A, R1B, R3A, or R3B via a ligand; and when the TLR7 agonist has Formula XX', the TLR7 agonist is Petition 870250096077, dated 10 / 21 / 2025, page 80 / 378 76 / 297 coupled to the targeting fraction in one of RIA, RIB, R3A or R3B by means of a binder. [000149] In certain embodiments, a compound is provided comprising a targeting moiety comprising a folate ligand or a functional fragment or analogue thereof linked to an immune modulator comprising a TLR agonist via a ligand, the TLR agonist having the following structure represented by formula XXX: (XXX) where R1 is an amine group, R2 is a single -NH- bond, and R3 is an H, an alkyl, a hydroxyl group or any other substituted group thereof, X is a CH2, NH, O or S, and the ligand is attached to R1, R2 or R3. Additionally or alternatively, R1 may be -NH2 or -NH-R1X; R2 may be an H, an alkyl, an alkenyl, an alkynyl, an alicyclic, an aryl, a biaryl, a heteroaryl, -NH-R2X, -O-R2X, -S-R2X, R2XR2X —N — N JR2YR2Y or ; each of RIX, R2X and R2Y may be selected independently from the group consisting of an H, an alkyl, an alkenyl, an alkynyl, an alicyclic, an aryl, a biaryl and a Petition 870250096077, dated 10 / 21 / 2025, p. 81 / 378 heteroaryl; it can be a non-aromatic mono- or bicyclic heterocycle of 3 to 10 members containing N; and / or X can be CH, CR2 or N. [000150] In some embodiments, a pharmaceutical composition is provided comprising any formula or compound provided, wherein the linker comprises PEG or a PEG derivative and, in some cases, is a non-releasable linker linked to R3 or is a releaseable linker linked to RI, R2 or R3. [000151] In some embodiments, the immunomodulatory group (e.g., TLR7 or TLR 7 / 8 agonist) of a compound is a radical with a Formula XXX structure and, more specifically, Formula XXX': R1C 1 η where, R1C is -NH2 or -NH-R1X, R2C is a bond, NH, -NR1X or CH2, Xa R3E (XXX') Petition 870250096077, dated 10 / 21 / 2025, p. 82 / 378 78 / 297, if applicable, is a non-aromatic, N-containing mono- or bicyclic heterocycle with 3 to 10 members; XA is CH2, NH2, or -NH-R1X; and each R1X is independently selected from the group consisting of an H, an alkyl, an alkenyl, an alkynyl, an alicyclic, an aryl, a biaryl, and a heteroaryl, where the TLR7 agonist is conjugated to the target moiety in one of the RIC, R2C or R3B via a ligand. [000152] One embodiment provides a compound represented by the structure of Formula (2-II): Formula ¢2-11) or a pharmaceutically acceptable salt or hydrate thereof, where: R1, R3, R4, R5 are each independently an H, an alkyl, an alkoxyl, an alkenyl, an alkynyl, an alicyclic, an aryl, Petition 870250096077, dated 10 / 21 / 2025, p. 83 / 378 79 / 297 π Ο a biaryl, a halo, a heteroaryl, -C0R2x, ín =ouR2y R2 is H, -OH, -NH2, -NHR2x, N3, -NH-CH2-NH2, -CONH2, SO2NH2, -NH-CS-NH2, or is a group of the formula GL-, G-0-, GLO-, GLO-alkyl-, GL-S-, G-S02-NH-, GL-NRaRb-, GLS(O)x-alkyl-, GL-CO-, GL-aryl-, G-LNH-CO-NH-, GL-NH-O-, GL-NHNH-, GL-NH-CS-NH, GLC(O)-alkyl-, G L-SO2-, in which: L is a ligand and G is a ligand that binds to the folate receptor. Ra and Rb are each independently H, halo, hydroxy, alkoxy, aryl, amino, acyl, or C(O)Rc, where Re is alkyl, aryl, oxy, or alkoxy; x is 0.3; each of R2x and R2y is independently selected from the group consisting of H, -OH, -CH2-OH, -NH2, -CH2-NH2, -COOMe, COOH, -CONH2, -COCH3, alkyl, alkenyl, alkynyl, alicyclic, aryl, biaryl, and heteroaryl, and Petition 870250096077, dated 10 / 21 / 2025, p. 84 / 378 80 / 297 each R2z is independently selected from the group consisting of -NH2, -NR2qR2q', -O-R2q, -SO-R2q and -COR2q; where each R2q and R2q' is independently alkyl or H, It is a non-aromatic, mono- or bicyclic heterocycle containing N, with 3 to 10 members; where, in Formula 2-II, X1, X2 and X3 are each independently CRq or N; each Rq is independently hydrogen, halogen or an optionally substituted alkyl; and where, in Formula 2-II, n is 0.30 and is 0.4. [000153] At least one embodiment provides an immune modulator (or radical thereof) represented by the structure of Formula (2-IIA) or a pharmaceutically acceptable salt or hydrate thereof: Formula (2-IIA) where: RI is optionally substituted alkyl (e.g., acyclic or cyclic) (e.g., optionally substituted by one or more substituents, each substituent being independently a halogen, Petition 870250096077, dated 10 / 21 / 2025, p. 85 / 378 81 / 297 alkyl, heteroalkyl, alkoxy or cycloalkyl); R2 is H, -ORz, -SO2N(Rz)2, -NR2xR2y or N3 and: R2x and R2y are each independently hydrogen, N(Rz)2, -CON(Rz)2, -C(Rz)2-N(Rz)2, -CS-N(Rz)2 or optionally substituted alkyl (for example, optionally substituted by one or more substituents, each substituent being independently oxo, halogen, alkyl, heteroalkyl, alkoxy or cycloalkyl); and each Rz is independently hydrogen, halogen or optionally substituted alkyl; or R2x and R2y are taken together to form an optionally substituted heterocycloalkyl (for example, wherein the optionally substituted heterocycloalkyl is a mono- or bicyclic heterocycloalkyl and / or wherein the optionally substituted heterocycloalkyl is a 3- to 10-membered heterocycloalkyl); each R3 is independently halogen, -N3, -CN, -NO2, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, heteroaryl, heterocycloalkyl, amino, hydroxyl, carbonyl or thiol, wherein alkyl, alkoxy, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted; R4 and R5 are each independently alkyl, alkoxy, halogen, or cycloalkyl, wherein the alkyl, alkoxy, and cycloalkyl are optionally substituted; Each of X1, X2, and X3 is independently CRq or N, and each Rq is independently hydrogen, halogen, or optionally substituted alkyl; Petition 870250096077, dated 10 / 21 / 2025, p. 86 / 378 82 / 297 Z is LG, where L is a ligand and G is a folate receptor-binding ligand; en is 1-6, em is 0-4. [000154] At least one embodiment provides an immune modulator (or radical thereof), or a pharmaceutically acceptable salt or hydrate thereof, having the structure of Formula (2II) or (2-IIA), where n is 1-30. In one embodiment, n is 1-6. In another embodiment, n is 1-3. In another embodiment, n is 1 or 2. In another embodiment, n is 0. In another embodiment, n is 1. [000155] At least one embodiment provides an immune modulator (or radical thereof), or a pharmaceutically acceptable salt or hydrate thereof, having the structure of Formula (2II) or (2-IIA), wherein R1 is an optionally substituted alkyl. In one embodiment, R1 is an optionally substituted C3-C6 alkyl. In another embodiment, R1 is an optionally substituted acyclic C3-C6 alkyl. In at least one embodiment, R1 is butyl. [000156] At least one embodiment provides an immune modulator (or radical thereof), or a pharmaceutically acceptable salt or hydrate thereof, having the structure of Formula (2II) or (2-IIA), wherein R2 is -NR2xR2y. In at least one embodiment, R2 is NH2. [000157] One embodiment provides an immune modulator (or radical thereof), or a pharmaceutically acceptable salt or hydrate thereof, having the structure of Formula (2-II) or (2-IIA), where R3 is H. [000158] At least one embodiment provides an immune modulator (or radical thereof), or a pharmaceutically acceptable salt or hydrate thereof, having the structure of Formula (2II) or (2-IIA), wherein R4 is alkyl. In at least one embodiment, R4 is methyl. Petition 870250096077, dated 10 / 21 / 2025, p. 87 / 378 83 / 297 [000159] At least one embodiment provides an immune modulator (or radical thereof), or a pharmaceutically acceptable salt or hydrate thereof, having the structure of Formula (2II) or (2-IIA), wherein R5 is alkyl. In at least one embodiment, R5 is methyl. [000160] At least one embodiment provides an immune modulator (or radical thereof), or a pharmaceutically acceptable salt or hydrate thereof, having the structure of Formula (2II) or (2-IIA), wherein R4 and R5 are each alkyl. In at least one embodiment, R4 and R5 are each methyl. [000161] At least one embodiment provides an immune modulator (or radical thereof), or a pharmaceutically acceptable salt or hydrate thereof, having the structure of Formula (2II) or (2-IIA), wherein m is 0. In another embodiment, m is 1. In another embodiment, m is 2. In another embodiment, m is 3. In another embodiment, m is 4. [000162] At least one embodiment provides an immune modulator (or radical thereof), or a pharmaceutically acceptable salt or hydrate thereof, having the structure of Formula (2II) or (2-IIA), wherein X1, X2 and X3 are each N. In at least one embodiment, X1 is N. In another embodiment, X2 is N. In at least another embodiment, X3 is N. [000163] At least one embodiment provides an immune modulator (or radical thereof) having the structure of Formula (2-II) or (2-IIA), wherein the compound is represented by the structure: Petition 870250096077, dated 10 / 21 / 2025, p. 88 / 378 84 / 297 OR Petition 870250096077, dated 10 / 21 / 2025, p. 89 / 378 85 / 297 is either a pharmaceutically acceptable salt or hydrate of either of the preceding structures. [000164] At least one embodiment provides an immune modulator (or radical thereof) represented by the structure of Formula (2-III): Formula (2-IΠ) or a pharmaceutically acceptable salt or hydrate thereof, wherein: R1, R3, R4 and R5 are each independently an H, an alkyl, an alkoxy, an alkenyl, an alkynyl, an alicyclic, an aryl, an biaryl, a halo, a heteroaryl, -COR2x,=θ'30) , or n-r2“ R^ wherein each of R2x and R2y is independently selected from the group consisting of H, -OH, -CH2-OH, -NH2, -CH2NH2, -COOMe, -COOH, -CONH2, -COCH3, alkyl, alkenyl, alkynyl, alicyclic, aryl, biaryl and heteroaryl, and each R2z is independently selected from the group consisting of -NH2, -NR2xR2y, -O-R2x, -SO-R2x and -COR2x; Petition 870250096077, dated 10 / 21 / 2025, p. 90 / 378 86 / 297 Z is a group of the formula GL-, GL-CO-, GLC(O)-alkyl-, where L is a ligand and G is a ligand binding to the folate receptor; and each of X1, X2 and X3 is independently CRq or N, and each Rq is independently hydrogen, halogen or optionally substituted alkyl; where, in Formula 2-III, n is 0-30 and is 0-4. [000165] At least one embodiment provides an immune modulator (or radical thereof) represented by the Formula (2-IIIA) structure, or a pharmaceutically acceptable salt or hydrate thereof: Formula (2-IIIA) where: RI is optionally a substituted alkyl (e.g., acyclic or cyclic) (e.g., optionally substituted by one or more substituents, each substituent independently being a halogen, alkyl, heteroalkyl, alkoxy, or cycloalkyl); Y is a ligand binding point or targeting part of the compound and comprises H, -ORz, -NR2xR2y, -SRz, -SORz, -SO3Rz, -N3, -CORz, -COORz, -CONRz2, -COSRz, -SO2N(Rz)2 or -CON(Rz)2; where: Petition 870250096077, dated 10 / 21 / 2025, p. 91 / 378 87 / 297 R2x and R2y are each independently H, -N(Rz)2, CON(Rz)2, -C(Rz)2-N(Rz)2, -CS-N(Rz)2, or optionally substituted alkyl (for example, optionally substituted by one or more substituents, each substituent independently being oxo, halogen, alkyl, heteroalkyl, alkoxy, or cycloalkyl); each Rz is independently H, a halogen, or an optionally substituted alkyl; or R2x and R2y are taken together to form an optionally substituted heterocycloalkyl (for example, where the optionally substituted heterocycloalkyl is a mono- or bicyclic heterocycloalkyl and / or where the optionally substituted heterocycloalkyl is a 3- to 10-membered heterocycloalkyl); Each R3 is independently a halogen, -N3, -CN, NO2, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, heteroaryl, heterocycloalkyl, amino, hydroxyl, carbonyl, or thiol, wherein the alkyl, alkoxy, heteroalkyl, cycloalkyl, or heterocycloalkyl group is optionally substituted; R4 and R5 are each independently alkyl, alkoxy, halogen, or cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl is optionally substituted; Each X1, X2, and X3 are independently CRq or N, and each Rq is independently H, halogen, or an optionally substituted alkyl group; Z is LG, where L is a ligand and G is a ligand that binds to the folate receptor; en is 1-6 and em is 0-4. Petition 870250096077, dated 10 / 21 / 2025, p. 92 / 378 88 / 297 [000166] At least one embodiment provides an immune modulator (or radical thereof), or a pharmaceutically acceptable salt or hydrate thereof, having the structure of Formula (2III) or (2-IIIA), where n is 1-30. In one embodiment, n is 1-6. In another embodiment, n is 1-3. In another embodiment, n is 1 or 2. In another embodiment, n is 0. In another embodiment, n is 1. In another embodiment, n is 1 and Y is OH. In another embodiment, n is 1 and Y is NH2. [000167] At least one embodiment provides an immune modulator (or radical thereof), or a pharmaceutically acceptable salt or hydrate thereof, having the structure of Formula (2III) or (2-IIIA), wherein Y is OH. [000168] At least one embodiment provides an immune modulator (or radical thereof), or a pharmaceutically acceptable salt or hydrate thereof, having the structure of Formula (2III) or (2-IIIA) wherein Y is NH2. [000169] At least one embodiment provides an immune modulator (or radical thereof), or a pharmaceutically acceptable salt or hydrate thereof, having the structure of Formula (2III) or (2-IIIA) wherein n is 1 and Y is OH. [000170] At least one embodiment provides an immune modulator (or radical thereof), or a pharmaceutically acceptable salt or hydrate thereof, having the structure of Formula (2III) or (2-IIIA) wherein n is 1 and Y is NH2. [000171] At least one embodiment provides an immune modulator (or radical thereof), or a pharmaceutically acceptable salt or hydrate thereof, having the structure of Formula (2III) or (2-IIIA) wherein n is 0 and Y is NH2. [000172] At least one modality provides an immune modulator (or radical thereof), or a salt or carbohydrate Petition 870250096077, dated 10 / 21 / 2025, p. 93 / 378 89 / 297 pharmaceutically acceptable thereof, having the structure of Formula (2III) or (2-IIIA), wherein R1 is an optionally substituted alkyl. In at least one embodiment, R1 is an optionally substituted C3-C6 alkyl. In another embodiment, R1 is an optionally substituted acyclic C3-C6 alkyl. In at least one other embodiment, R1 is butyl. [000173] At least one embodiment provides an immune modulator (or radical thereof), or a pharmaceutically acceptable salt or hydrate thereof, having the structure of Formula (2III) or (2-IIIA), where R3 is H. [000174] At least one embodiment provides an immune modulator (or radical thereof), or a pharmaceutically acceptable salt or hydrate thereof, having the structure of Formula (2III) or (2-IIIA), wherein R4 is alkyl. In at least one embodiment, R4 is methyl. [000175] At least one embodiment provides an immune modulator (or radical thereof), or a pharmaceutically acceptable salt or hydrate thereof, having the structure of Formula (2III) or (2-IIIA), wherein R5 is alkyl. In at least one embodiment, R5 is methyl. [000176] At least one embodiment provides an immune modulator (or radical thereof), or a pharmaceutically acceptable salt or hydrate thereof, having the structure of Formula (2III) or (2-IIIA), wherein R4 and R5 are each alkyl. In at least one embodiment, R4 and R5 are each methyl. [000177] At least one embodiment provides an immune modulator (or radical thereof), or a pharmaceutically acceptable salt or hydrate thereof, having the structure of Formula (2III) or (2-IIIA), wherein m is 0. In another embodiment, m is 1. In another Petition 870250096077, dated 10 / 21 / 2025, p. 94 / 378 In one modality (90 / 297), m is 2. In another modality, m is 3. In yet another modality, m is 4. [000178] At least one embodiment provides an immune modulator (or radical thereof), or a pharmaceutically acceptable salt or hydrate thereof, having the structure of Formula (2III) or (2-IIIA), wherein XI, X2 and X3 are each N. In at least one embodiment, XI is N. In another embodiment, X2 is N. In another embodiment, X3 is N. [000179] In some modalities, the immune modulator (or radical thereof) is represented by one or more of the following structures: It is either a pharmaceutically acceptable salt or carbohydrate thereof. [000180] In some modalities, the immune modulator (or radical thereof) is represented by one or more of the following structures: Petition 870250096077, dated 10 / 21 / 2025, p. 95 / 378 91 / 297 It is either a pharmaceutically acceptable salt or hydrate of either of the preceding structures. [000181] Target Fractions [000182] As described previously, immunomodulators (or their radicals), including the compound TLR-7 / 8, can be conjugated to a target fraction (e.g., via a ligand). [000183] The compound may further comprise a target moiety (or a radical thereof) linked to the immune modulator (or a radical thereof) that targets a pattern recognition receptor or a DAMP of a cell. [000184] The toxicities associated with the systemic administration of at least some of the conventional immunomodulators identified here have historically prevented their practical application in the treatment of cancers. For example, TLR agonists cannot be Petition 870250096077, dated 10 / 21 / 2025, page 96 / 378 92 / 297 tolerated by an individual and, in some cases, may result in the death of a subject (for example, if administered systemically via conventional modalities). In some modalities, the compounds, such as those with Formulas I and / or II, are significantly more potent than conventional medications that can be used with the compounds and, in some cases, a mechanism to circumvent systemic toxicity is preferable. [000185] In some embodiments, the targeting fraction comprises a ligand that targets a specific area or tissue of an individual (e.g., with high specificity) and, in certain cases, may, for example, comprise hormones, antibodies and / or vitamins. [000186] In certain embodiments, the targeting fraction comprises a folate ligand or a functional fragment or analogue thereof. “Folate” means a folate receptor-binding molecule, including, for example, folic acid and folic acid analogues and derivatives, such as, without limitation, folinic acid, pteroylpolyglutamic acid, pteroyl-D-glutamic acid and folate receptor-binding pterdins, such as tetrahydropterins, dihydrofolates, tetrahydrofolates and their analogues deaza and dideaza. [000187] The analogous terms “deaza” and “dideaza” refer to analogs recognized in the art that have one carbon atom substituted by one or two nitrogen atoms in the natural structure of folic acid, or an analog or derivative thereof. For example, deaza analogs may include 1-deaza, 3-deaza, 5-deaza, 8-deaza, and 10-deaza analogs of folate, folinic acid, pteropolyglutamic acid, and folate receptor-binding pteridines such as tetrahydropterins, dihydrofolates, and tetrahydrofolates. Dideaza analogs include, for example, 1,5-dideaza, 5,10-dideaza, 8,10-dideaza, and 5,8-dideaza analogs of folate. Other folates useful as complex-forming ligands are the Petition 870250096077, dated 10 / 21 / 2025, page 97 / 378 93 / 297 folate receptor-binding analogs pemetrexed, proguanil, pyrimethamine, trimethoprim, pralatrexate, raltitrexed, aminopterin, amethopterin (also known as methotrexate), N10-methylfolate, 2-desamino-dihydroxyfolate, deaza analogs, such as 1-desamethopterin or 3-desamethopterin, and 3',5'-dichloro-4-amino-4-deoxy-N10-methylpteroylglutamic acid (dichloromethotrexate). [000188] Folic acid and the above analogues and / or derivatives are also referred to as “a folate”, “the folate” or “folates”, reflecting their ability to bind to folate receptors. Folic acid is a member of the B vitamin family and may play an essential role in cell survival, for example, by participating in the biosynthesis of nucleic acids and amino acids. Folic acid can increase the specificity of conjugated immunomodulatory drugs targeting activated myeloid cells, and of conjugated anticancer drugs targeting folate receptor-positive cancer cells. These molecules, when conjugated with exogenous molecules, can be effective in increasing transmembrane transport, such as through folate-mediated endocytosis. The above can be used in the folate receptor-binding ligands described herein. [000189] In at least one embodiment, the targeting fraction comprises a molecule that has (e.g., high) affinity for the folate beta receptor (FR3). In some cases, the targeting fraction has a specific affinity for any receptor that is particular to cancer cells or tissues. [000190] KKβ can be significantly upregulated in activated myeloid cells (e.g., predominantly activated monocytes and M2-type macrophages), for example, with recorded data showing that KKβ is induced only in cells of myelogenous origin after exposure to anti-inflammatory or pro-inflammatory stimuli. Petition 870250096077, dated 10 / 21 / 2025, page 98 / 378 94 / 297 inflammatory. The folate receptor can be upregulated in (e.g., more than 90%) of non-mucinous ovarian carcinomas. In certain cases, the folate receptor is present in kidney, brain, lung, and breast carcinomas. For example, although there are several types of cancer that do not express the folate receptor in sufficient numbers to provide the desired specificity, cancerous tumors express myeloid-derived suppressor cells (MDSCs), for example, which express FR3 and, for example, can be targets of a targeting fraction provided here. In some modalities, folate receptors are not substantially present (e.g., present only at extremely low levels) in healthy (non-myeloid) tissues (e.g., lungs, liver, spleen, heart, brain, muscles, intestines, pancreas, bladder, etc.).In some cases, even macrophages residing in quiescent tissues, abundant throughout the body, are predominantly FRβ-negative. In some cases, uptake of folate-targeted imaging agents occurs, for example, in inflamed tissues, malignant lesions, and kidneys. In certain cases, individuals without cancer retain folate-targeted drugs only in the kidneys and sites of inflammation. In some cases, the discrepancy in folate receptor expression provides a mechanism to selectively target fibrotic cancer cells. [000191] The compounds can leverage the limited expression of FRβ to target / localize potent systemically administered immunomodulators (e.g., from the compounds) in fibrotic and / or cancerous tissue. The compounds can be administered directly to cells expressing FRβ, for example, which advantageously prevents systemic activation of the immune system and, for example, can avoid (e.g., at least a part of) the toxicity that previously prevented the systemic use of non-targeted compounds (by Petition 870250096077, dated 10 / 21 / 2025, page 99 / 378 95 / 297 example, drugs). [000192] In some cases, compounds comprising a folate ligand (or radical thereof), or a functional fragment or analogue thereof, as a targeting moiety and an immune modulator (e.g., TLR7, TLR8, TLR7 / 8, TLR9, or TLR3 agonist) are provided. In some cases, TLR7, TLR8, TLR7 / 8, TLR9, and TLR3 are present in the endosome. In some embodiments, the compound, or its radical, binds to a TLR. In some embodiments, the TLR is TLR7. [000193] A pyrido[2,3-d]pyrimidine analog ligand (e.g., or its radical), a functional fragment or analog, or any other molecule, fragment, or atom with affinity (e.g., and without limitation, high specificity) for FRp may alternatively be used as the target fraction (or its radical). For example, folate analog molecules may have a relative affinity for binding to FRp of about 0.01 or greater compared to folic acid at a temperature of about 20 °C / 25 °C / 30 °C / physiological. Similarly, a Galectin-3 ligand, a translocator protein (TSPO) ligand, and any other ligand or targeting fraction with highly specific affinity for cancerous cells or tissues may be employed. [000194] Specific examples of suitable targeting fractions (or radicals thereof) will be provided below; however, it should be understood that the targeting fraction (or radical thereof) may comprise any ligand (or radical thereof) useful for targeting pFR and is not limited to the structures specified herein. The ligand (or radical thereof) may bind to pFR. [000195] In certain embodiments, a compound may include a directing moiety (or radical thereof) having a Formula V structure or a functional fragment or analogue thereof: Petition 870250096077, dated 10 / 21 / 2025, p. 100 / 378 96 / 297 in what XI, X2, X3, X4, X5, X6, X7, X8 and X9 are each independently N, NH, CH, CH2, O or S; Y is C, CH, CH2, N, NH, O or S; Z stands for glutamic acid, valine, or any other amino acid; RI and R2 are each independently NH2, OH, SH, CH3, or H; R3 is H or an alkyl group; The letters 'men' and 'men' are, each independently, 0 or 1; and 'e' is representative of a single or double C-C bond. [000196] In an additional aspect, by way of example but not limitation, the directing fraction (or radical thereof) of Formula V has a VI structure (or a functional fragment or analogue thereof): Petition 870250096077, dated 10 / 21 / 2025, p. 101 / 378 97 / 297 in what XI, X2, X3, X5, X6, X7, X8 and X9 are each independently N, NH, CH, CH2, O or S; Y is C, CH, CH2, N, NH, O or S; Z stands for glutamic acid, valine, or any other amino acid; R1 and R2 are each independently NH2, OH, SH, CH3, or H; R3 is H or an alkyl group; The letters 'men' and 'men' are, each independently, 0 or 1; and 'e' is representative of a single or double C-C bond. [000197] Another specific targeting fraction (or radical thereof) of Formula V (or a functional fragment or analogue thereof) has a Formula VII structure: Petition 870250096077, dated 10 / 21 / 2025, p. 102 / 378 98 / 297 in what XI, X2, X3, X4, X5, X6, X7, X8 and X9 are each independently N, NH, CH, CH2, O or S; Y is C, CH, CH2, N, NH, O or S; Z stands for glutamic acid, valine, or any other amino acid; R1 and R2 are each independently NH2, OH, SH, CH3, or H; R3 is H or an alkyl group; The letters 'men' and 'men' are, each independently, 0 or 1; and 'e' is representative of a single or double C-C bond. [000198] In some categories, the steering fraction (or radical thereof) of Formula VI has the structure of Formula VIII: Petition 870250096077, dated 10 / 21 / 2025, p. 103 / 378 99 / 297 in what XI, X2, X3, X5, X6, X7, X8 and X9 are each independently N, NH, CH, CH2, O or S; Y is C, CH, CH2, N, NH, O or S; Z stands for glutamic acid, valine, or any other amino acid; RI and R2 are each independently NH2, OH, SH, CH3, or H; R3 is H or an alkyl group; m is 0 or 1; and e is representative of a single or double DC bond. [000199] In some categories, the steering section (or its radical) of Formula VI has the structure of Formula IX: Petition 870250096077, dated 10 / 21 / 2025, p. 104 / 378 100 / 297 where XI, X2, X3, X5, X6, X7, X8 and X9 are each independently N, NH, CH, CH2, O or S; Y is C, CH, CH2, N, NH, O or S; Z stands for glutamic acid, valine, or any other amino acid; RI and R2 are each independently NH2, OH, SH, CH3, or H; R3 is H or an alkyl group; m is 0 or 1; and e is representative of a single or double DC bond. [000200] In some modalities, the steering fraction (or radical thereof) of Formula VII has the structure of Formula X'” or XI: Petition 870250096077, dated 10 / 21 / 2025, p. 105 / 378 101 / 297 in what XI, X2, X3, X4, X5, X6, X7, X8 and X9 are each independently N, NH, CH, CH2, O or S; Y is C, CH, CH2, N, NH, O or S; Z stands for glutamic acid, valine, or any other amino acid; RI and R2 are each independently NH2, OH, SH, CH3, or H; R3 is H or an alkyl group; m is 0 or 1; and It is representative of a single or double DC connection; or Petition 870250096077, dated 10 / 21 / 2025, p. 106 / 378 102 / 297 where XI, X2, X3, X4, X5, X6, X7, X8 and X9 are each independently N, NH, CH, CH2, O or S; Y is C, CH, CH2, N, NH, O or S; Z stands for glutamic acid, valine, or any other amino acid; RI and R2 are each independently NH2, OH, SH, CH3, or H; R3 is H or an alkyl group; m is 0 or 1; and e is representative of a single or double DC bond. [000201] Chemical structures and spectroscopic data of some additional embodiments of a targeting fraction (e.g., or its radicals) are provided in Tables 3, 4, 5 and 6 below. [000202] Table 3 provides non-limiting examples of additional embodiments of a targeting fraction (e.g., or its radicals) with the structure of Formula VIII. [000203] Table 3. Formula VIII Binder Structure Petition 870250096077, dated 10 / 21 / 2025, p. 107 / 378 103 / 297 Petition 870250096077, dated 10 / 21 / 2025, p. 108 / 378 104 / 297 Petition 870250096077, dated 10 / 21 / 2025, p. 109 / 378 105 / 297 i 9 CO;H HN I] > <s. y rr x em que X é N ou CH; Y é NH2, H ou CH3; e Ré H, CH3 ou CHO j em que X é OH ou OCH3; R é H ou CH3; e Y é ácido glutâmico, valina ou qualquer outro aminoácido. Petition 870250096077, dated 10 / 21 / 2025, p. 110 / 378 106 / 297 [000204] Table 4 provides non-limiting examples of additional embodiments of a directing fraction (e.g., or radicals thereof) with the structure of Formula IX. [000205] Table 4. Formula IX Petition 870250096077, dated 10 / 21 / 2025, p. 111 / 378 107 / 297 [000206] Table 5 provides non-limiting examples of additional modalities of a targeting fraction with the Formula structure. [000207] Table 5. Formula X'” Petition 870250096077, dated 10 / 21 / 2025, p. 112 / 378 108 / 297 [000208] As noted previously, instead of folate, the target moiety (e.g., a radical thereof) may be one or more non-classical antifolate analogs, such as, for example, pyrido[2,3-d]pyrimidine or similar analogs (or radicals thereof) with the formulas (e.g., radicals of the formulas) presented in Table 6 below (or an analog or functional fragment thereof): Petition 870250096077, dated 10 / 21 / 2025, page 113 / 378 109 / 297 [000209] Table 6. Non-classical antifolate analogues Petition 870250096077, dated 10 / 21 / 2025, page 114 / 378 110 / 297 0CH3; R2 is an H or alkyl chain or CHO; and is representative of a single or double C-C bond. cccc nh2 r2 JL AJ r2 HN NN 2 where n is 0 or 1; RI and R2 are each independently an H or an alkyl; and R3 is an H or 3',4',5'-OMe or 2',3',4'-OMe or 2',4',5'-OMe or 2',4',6'-OMe or 3',4'-OMe or 3',5'-OMe or 2',5'-OMe or 2',3'-C4H4 or 4'OMe,2',3'-C4H4 or 6'-OMe,2',3'-C4H4 or 4'O-C6H5 or 4'-CONH-L-glutamic acid. Petition 870250096077, dated 10 / 21 / 2025, p. 115 / 378 111 / 297 Petition 870250096077, dated 10 / 21 / 2025, p. 116 / 378 112 / 297 Petition 870250096077, dated 10 / 21 / 2025, p. 117 / 378 113 / 297 hhhh where R is H, 4-C1, 2-CH3O, 4-CH3O, 2,4-(CH3O)2, 4CH3 or 4-C6H5O. iiii MS . -N n R * . μ '0 S o CH' where R is H, 4-C1, 2-CH3O, 4-CH3O, 2,4-(CH3O)2, 4-CH3 or 4-C6H5O. Petition 870250096077, dated 10 / 21 / 2025, p. 118 / 378 114 / 297 jjjj r3 r, NH2 A.„R2 ii J γ HSN .k r4 where R1 and R2 are each independently H or OMe; R3 is H or an alkyl; and R4 is o-COOH or m-COOH or p-COOH. kkkk NHSR3 aY7 O'”1 H;NN N�' where R1 is H or 2'-OMe or 4'-OMe or 2',5'-dioMe or 3',4',5'-triOMe or 4'-Me or 4'-i-Pr or 3',4'(C4H4) or 2',3'-(C4H4) or 4'-NO2 or 2',5'-diF or 3',4',5'—triF; and R2 is H or an alkyl. Petition 870250096077, dated 10 / 21 / 2025, p. 119 / 378 115 / 297 [000210] A compound, or a pharmaceutically acceptable salt thereof, is provided with the structure of Formula (2-II), (2-IIA), (2-III) or (2-IIIA) (described above), where G is a folate receptor-binding ligand. In one embodiment, G is or is derived from folate, folic acid, or a functional fragment or derivative thereof. In one embodiment, G is a folate or folate derivative. In another embodiment, G is a pteroic acid or pteroyl derivative. [000211] An embodiment provides a compound, or a pharmaceutically acceptable salt or hydrate thereof, having the embodiment of structure Formula (2-II), (2-IIA), (2-III) or (2-IIIA) where G is a group or comprises a group of Formula (2-IV): Petition 870250096077, dated 10 / 21 / 2025, p. 120 / 378 116 / 297 where R is a natural or non-natural amino acid, or its derivative or fragments. [000212] One embodiment provides a compound, or a pharmaceutically acceptable salt or hydrate thereof, having the structure of Formula (2-II), (2-IIA), (2-III) or (2-IIIA)) where G is a group or comprises a group of Formula (2-V): Formula (2-V). [000213] One embodiment provides a compound, or a pharmaceutically acceptable salt or hydrate thereof, having the structure Formula (2-II), (2-IIA), (2-III) or (2-IIIA) where G is a group or comprises a group of Formula (2-VI): Formula (2ΛT) Petition 870250096077, dated 10 / 21 / 2025, p. 121 / 378 117 / 297 [000214] Binders [000215] A compound may comprise one or more ligands, wherein a radical of the target moiety is conjugated to a radical of the immune modulator by means of one or more ligands. The term “ligand” includes a chain of atoms that is biofunctionally adapted to form a chemical bond with an A, B, or S and connects two or more functional moieties of a molecule to form the compound. Illustratively, the chain of atoms may be selected from carbon (C), N, oxygen (O), sulfur (S), silicon (Si), and phosphorus (P), or C, N, O, S, and P, or C, N, O, and S. The chain of atoms may covalently connect different functional capacities of the compound, such as a folate and the drug (i.e., immune modulator). [000216] The ligand may comprise a wide variety of linkages, such as in the range of about 2 to about 100 atoms in the contiguous main chain, and may comprise a releasable or non-releasable ligand. [000217] In some embodiments, a ligand comprises PEG, a PEG derivative, or any other ligand known in the art or subsequently developed that may accomplish the purpose set forth herein. In some embodiments, the compound further comprises a ligand (“L” or “Ln”) between or otherwise connecting the targeting fraction and the immunomodulator. In some embodiments, the Ln ligand is configured to prevent the release of the immunomodulator, n is an integer equal to or less than 50. In some embodiments, the Ln ligand comprises PEG or a PEG derivative, n is an integer selected in the range of 1 to 32, and the targeting fraction (e.g., a radical thereof) comprises a folate receptor-binding ligand radical comprising the FRp-binding ligand. In some embodiments, n is 1-50, 1-10, 2-8, or 2-4. [000218] In some forms, the ligand is repeated n times (“Ln”), Petition 870250096077, dated 10 / 21 / 2025, page 122 / 378 118 / 297 where n is a positive integer. For example, and without limitation, n can be any integer selected from the range 1-16, 1-32, 1-64 or 1-96. The number of repetitions in the binder can be selected to achieve the desired functionality, size and / or potency of the compound and / or in view of the intended application. [000219] The ligand is either releasable (i.e., “fast-release”) or non-releasable (i.e., “slow-release”). In some cases, the target for a compound comprising a non-releasable ligand is the endosome (e.g., of the cell of interest), for example, while the target for a releasable ligand, in some cases, is the endosome, the cytoplasm, or both (e.g., of the cell of interest). In some embodiments, L is a fast-release hydrolyzable ligand. In some embodiments, L is a slow-release non-hydrolyzable ligand. In some embodiments, L is an optionally substituted heteroalkyl. [000220] The terms “releasable” and “fast-release” (which are used interchangeably herein) in the context of a ligand mean a ligand that includes at least one linkage that can be cleaved (e.g., chemically or enzymatically hydrolyzed) to varying degrees under certain conditions and, in particular, can be fragmented or cleaved in less than about 1 week when under, or otherwise exposed to, certain metabolic, physiological, or cellular conditions that may initiate a linkage fragmentation or cleavage cascade (which may, for example, result in the release of one or more of the connected fractions through one or more parts of the ligand (e.g., targeting fraction and immune modulator)). A fast-release ligand may comprise, for example, a multivalent releasable linkage that is labile to a reducing agent, labile to pH, labile to acid, labile to base, labile to oxidation, labile to metabolism, labile to biochemistry, labile to enzyme, or p-aminobenzyl base. Petition 870250096077, dated 10 / 21 / 2025, p. 123 / 378 119 / 297 [000221] The cleavage of the bond can occur by standard chemical hydrolysis reactions that occur, for example, at physiological pH, or as a result of compartmentalization in a cellular organelle, such as an endosome with a pH lower than the cytosolic pH. The cleavage of the bond can also occur by acid-catalyzed elimination. Alternatively, fragmentation can be initiated by a nucleophilic attack on a disulfide group of the fast-release ligand, causing cleavage to form a thiolate, for example. In any of these cases, the fast-release nature of such ligands can be achieved by any mechanism that is relevant to the chemical, metabolic, physiological, or biological conditions present. In certain embodiments, a fast-release ligand comprises one or more sulfide bridges. In some cases, the releasable ligand is broken into two or more fragments. In some cases, the releasable ligand is separated from the target fraction.In some modalities, the targeting fraction and the immune modulator are released from each other, and the immune modulator becomes active. [000222] In contrast, the terms “non-releasable” and “slow-release” (which are used interchangeably herein) in the context of a ligand mean a ligand that includes at least one bond that is not easily or rapidly broken (i.e., the bond does not cleaves) and, while potentially cleavable or fragmentable to varying degrees under certain conditions, does not otherwise cleave, fragment, or release one or more of the connected fractions through one or more parts of the ligand (e.g., targeting fraction and immune modulator) when subjected to certain metabolic, physiological, or cellular conditions that may initiate a fragmentation cascade (e.g., after administration to a subject) for more than about 1 week (e.g., 1 week), more than about 1 month (e.g., 1 month), more than about 4 months (e.g., 4 months), more than about 6 months (e.g., 6 Petition 870250096077, dated 10 / 21 / 2025, p. 124 / 378 120 / 297 months) or more than about 1 year (e.g., 1 year). In certain embodiments, a slow-release ligand comprises one or more amide linkages. [000223] In some embodiments, a compound comprises a non-releasable ligand that does not release any component of the compound (e.g., a targeting ligand (e.g., a fully amorphous ligand (FA) or pteroyl amino acid) or an immune modulator (e.g., a TLR7 agonist)). In some embodiments, the non-releasable ligand lacks a disulfide linkage (e.g., SS) or an ester in the backchain. In some embodiments, the compound comprises a targeting moiety and an immune modulator connected by a backchain that is substantially stable throughout the duration of the compound's circulation in an individual (e.g., during endocytosis in the target cell endosome).In some embodiments, a compound comprising the non-releasable ligand is particularly beneficial when the immune modulator targets TLRs, NOD-like receptors, and / or other pattern recognition receptors present in the endosome of a cell. The non-releasable ligand may comprise: an amide, an ester, an ether, an amine, and / or a thioether (e.g., thio-maleimide). Although specific examples are provided here, it should be understood that any molecule may be used in the non-releasable ligand, provided that it forms at least one bond that is not easily or rapidly broken under physiological conditions. [000224] Perhaps more specifically, in some embodiments, a non-releasable ligand comprises a ligand that, at neutral pH, for example, less than ten percent (10%) (e.g., less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.1%, less than 0.01% or less than 0.001%) will be hydrolyzed in an aqueous solution (e.g., buffered (e.g., phosphate buffer)) within Petition 870250096077, dated 10 / 21 / 2025, page 125 / 378 121 / 297 a period of time (e.g., 24 hours). In some embodiments, where a non-releasable ligand is employed, less than about ten percent (10%) and preferably less than five percent (5%) or none, of the administered compound releases the free drug (e.g., into the systemic circulation before uptake by target cells / tissues). In some embodiments where the compound comprises a non-releasable ligand, within one (1) hour after administration, less than five percent (5%) of the free drug is released from the compound while it is in the systemic circulation. [000225] In some embodiments, the targeting fraction does not separate from the drug / immunomodulator so that the compound is therapeutically effective in vivo. In some embodiments, this is advantageous as it allows the use of targeting compositions comprising potent drugs (e.g., TLR7 agonists), for example, because only a negligible amount (if any) of the drug (e.g., immunomodulator, e.g., TLR7 agonist) is released (e.g., systemically) before targeted administration of the compound. [000226] Adjusting the release properties of the active components of a compound can be a difficult aspect of preparing effective pharmaceutical compositions. Compounds comprising non-releasable ligands can avoid the difficulties of preparing effective pharmaceutical compositions (e.g., eliminating the need to time the release). In some embodiments, the immune modulator or warhead of the compound is active when bound (e.g., conjugated to the target compound). In some embodiments, while the warhead / immunomodulator is active, the non-releasable ligand and target fraction prevent the release of toxic cytokines (e.g., by the subject's body) that activate the immune system (such as, Petition 870250096077, dated 10 / 21 / 2025, page 126 / 378 122 / 297 for example, interleukin 6 (IL-6)) (for example, because the compound is specifically targeted (using, for example, folate or an analog thereof)). In certain cases, the immune modulator cannot access the appropriate receptor (e.g., target) within the cell's endosome until the compound binds to the target receptor (e.g., a folate receptor), for example, even if the compound's warhead / immune modulator is active when bound to the non-releasable ligand. [000227] By way of non-limiting example, ligand 106 of FIG. 1A is a non-releasable PEG ligand, while ligand 156 of FIG. 1B is a self-immolating and releasable ligand (e.g., comprising a disulfide linkage (e.g., SS)). For example, the diagram shown in FIG. 1B illustrates the self-immolating cascade of compound 150 after cleavage of target moiety 154. [000228] In some embodiments, the ligand 156 is formed in such a way that the drug (e.g., immunomodulator) is cleaved from the target moiety 154 only after sufficient time has passed for the compound to circulate in a subject's systemic circulation after administration (e.g., free from non-target tissues and captured and internalized by the target cell and / or receptor). In some embodiments, the release period varies (e.g., from individual to individual (e.g., based on a variety of factors)). In some embodiments, a releasable ligand is designed so that it is not cleaved / released until at least 24 hours after administration or even over a period of one week.In some modalities, the compound can safely pass through the individual's system, and any amount not captured by target cells (e.g., those expressing FR3) can be excreted before release / activation, thus avoiding toxicity (e.g., because the immunomodulator is not active when bound to a releasable ligand). [000229] Both releasable and non-releasable ligands can be Petition 870250096077, dated 10 / 21 / 2025, page 127 / 378 123 / 297 designed to optimize biodistribution, bioavailability, and pharmacokinetics / pharmacodynamics (e.g., of the compound) and / or to increase uptake (e.g., of the compound) in the target tissue, according to methodologies commonly known in the art or subsequently developed, such as by means of PEGlaytion and the like. In some embodiments, the ligand is configured to prevent significant release of a pharmaceutically active amount of the drug into circulation before uptake by a cell (e.g., a cell of interest (e.g., a macrophage in cancerous tissue to be treated)). [000230] In some embodiments, compounds comprising releasable ligands are designed to diffuse across the endosome membrane and, for example, into the cytoplasm of the target cell. In some embodiments, the releasable ligands are designed so that the immunomodulator is not released until the compound reaches the cytoplasm. [000231] In some embodiments, a compound comprises a releasable ligand (e.g., to facilitate the release of the immune modulator into the cytoplasm, for example, where the immune modulator comprises a PI3K kinase, IRAK, or an I-kappa-β (Iκβ) kinase activator (e.g., using Prostratin or similar) or an enhancer of the kappa light chain of activated B cell nuclear factor (NF-κβ) (see, for example, Table 1), or a primary myeloid differentiation response agonist 88 (MyD88)). In some embodiments, the releasable ligand prevents the release of the immune modulator, for example, until the targeting fraction binds to the appropriate target (e.g., a macrophage folate receptor) and is internalized into the target cell endosome and / or diffuses into the cytoplasm (e.g., where the desired pattern recognition receptor is located). In some modalities, the releasable ligand releases the immune modulator within the Petition 870250096077, dated 10 / 21 / 2025, page 128 / 378 124 / 297 endosomal. [000232] In some embodiments, the linker may comprise one or more spacers (for example, which may also be used to engineer specific characteristics of the compound, such as, for example, facilitating a specific release time, facilitating increased uptake in a target tissue, and / or optimizing the biodistribution, bioavailability, and / or PK / PD of a compound). A spacer may comprise one or more alkyl chains, PEGs, peptides, sugars, peptidoglycans, clickable linkers (e.g., triazoles), rigid linkers such as polyprolines and polypiperidines, and the like. [000233] In some embodiments, a ligand comprising PEG12 significantly reduces – if not completely prevents – the non-specific uptake of the compounds provided herein (e.g., in a non-target organ (e.g., in the liver and / or kidneys of an individual after administration)). In some embodiments, the compounds prevent administration to the liver and kidneys. In some embodiments, the targeting moieties (in their free form, a radical thereof, or a compound thereof) do not bind to uptake receptors on non-target cells (e.g., provided that the organs are not the target sites and, as such, immune complex stimulation in those organs can be avoided, which is highly beneficial in a clinical context). [000234] A compound comprising a non-releasable ligand may reduce or eliminate the toxicity of an immune modulator released from the compound in its free form (e.g., a free form of a compound and / or ligand provided herein). In certain embodiments, a compound, or a pharmaceutically acceptable salt or hydrate thereof, has or comprises the structure of Formulas (2-II), (2-IIA), (2-III) or (2-IIIA) described below, where L is a fast-release ligand (e.g., amide, ester, ether or sulfonamide). Petition 870250096077, dated 10 / 21 / 2025, p. 129 / 378 125 / 297 [000235] In another embodiment, L is an optionally substituted heteroalkyl. The term “heteroalkyl”, by itself or in combination with another term, means, unless otherwise indicated, a stable linear or branched chain, or combination(s) thereof, consisting of at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si and S, and in which the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The O, N, P, S and Si heteroatom(s) may be located in any internal position of the heteroalkyl group or in the position where the alkyl group is attached to the rest of the molecule. Examples include, but are not limited to, —CH2—CH2—O—CH3, —CH2—CH2—NH—CH3, —CH2—CH2—N(CH3)—CH3, —CH2—S—CH2—CH3, —CH2—CH2—S(O)—CH3, —CH2—CH2—S(O)2—CH3, —CH2=CH—O—CH3, —Si(CH3)3, —CH2—CH=N—OCH3, —CH=CH—N(CH3)—CH3, —O—CH2—CH3, and —CN.Up to two heteroatoms can be consecutive, such as —CH2—NH—OCH3. [000236] In some embodiments, the heteroalkyl is unsubstituted. In other embodiments, the heteroaryl is substituted by at least one substituent selected from the group consisting of alkyl, hydroxyl, acyl, oxo, PEG, carboxylate, and halo. “Halo” or “halogen”, alone or as part of another substituent, means, unless otherwise indicated, a fluorine, chlorine, bromine, or iodine atom. [000237] In another embodiment, L is a substituted heteroaryl with at least one disulfide bond in its main structure. [000238] In another embodiment, L is a peptide or a peptidoglycan with at least one disulfide linkage in its main structure. The terms “polypeptide,” “peptide,” and “protein” are used interchangeably herein to refer to a polymer of amino acid residues, a polypeptide, or a fragment of a polypeptide, peptide, or Petition 870250096077, dated 10 / 21 / 2025, page 130 / 378 126 / 297 fusion polypeptide. The terms apply to amino acid polymers in which one or more amino acid residues are an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymers. [000239] In some embodiments, L comprises -CONH-CH(COOH)CH2-SS-CH2-CRaRb-O-CO-, -CONH-CH(COOH)CRaRb-O-CO-, C(O)NHCH(COOH)(CH2)2-CONH-CH(COOH)CRaRb-O-CO- or C(O)NHCH(COOH)(CH2)2-CONH-CH(COOH)-CH2-SS-CH2-CRaRb-O-CO-, wherein Ra and Rb are independently H, alkyl or heteroalkyl (e.g., PEG). [000240] In another embodiment, L is a cleavable ligand that can be cleaved by enzymatic reaction, reactive oxygen species (ROS), or reductive conditions. [000241] In some embodiments, L has the formula: -NH-CH2-CR6R7S-S-CH2-CH2-O-CO-, wherein R6 and R7 are each independently H, alkyl or heteroalkyl. [000242] The ligand may further comprise a spacer. In certain embodiments, the spacer is a hydrophilic spacer. In some embodiments, the compound has the structure of Formula XII (for example, a substructure of the TLR7 agonist of Formula III conjugated with folate via a releasable ligand containing a first hydrophilic spacer): Petition 870250096077, dated 10 / 21 / 2025, page 131 / 378 127 / 297 It is either a pharmaceutically acceptable salt or carbohydrate thereof. [000243] In some embodiments, the compound has a Formula XIII structure (e.g., a Formula III TLR7 agonist substructure conjugated with folate via a non-releasable ligand (covalent bond) comprising a second hydrophilic spacer): Petition 870250096077, dated 10 / 21 / 2025, p. 132 / 378 128 / 297 It is either a pharmaceutically acceptable salt or carbohydrate thereof. [000244] In some forms, L is a group or comprises a group of the formula: Petition 870250096077, dated 10 / 21 / 2025, p. 133 / 378 129 / 297 where each * is a connection point; p is 0 to 30; ed is 1 to 40; and where R8 and R9 are each independently H, alkyl, cyclic, aryl, or heteroalkyl. [000245] One embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (2II), (2-IIA), (2-III) or (2-IIIA), where L is a non-cleavable ligand. [000246] One embodiment provides a compound, or a salt or hydrate Petition 870250096077, dated 10 / 21 / 2025, p. 134 / 378 130 / 297 pharmaceutically acceptable of the same, having the structure of Formula (2II), (2-IIA), (2-III) or (2-IIIA), where L is a non-hydrolyzable ligand. [000247] In some embodiments, L is selected from the group consisting of alkylene, heteroalkylene, -O-alkynylene, alkenylene, acyl, aryl, heteroaryl, amide, oxime, ether, ester, triazole, PEG and carboxylate. [000248] In one embodiment, L is an alkyl ether. In another embodiment, L is an amide. In another embodiment, L is a peptide or a peptidoglycan. In another embodiment, L is an amino acid. In another embodiment, L is a PEG (e.g., -OCH2-CH2-O-). In another embodiment, L is a polysaccharide. [000249] In some forms, L comprises a structure of: oo or where each is a connection point, and each is independently from 0 to 10. [000250] In some forms, the linker comprises a structure of: Petition 870250096077, dated 10 / 21 / 2025, pp. 135 / 378 131 / 297 COOH O . 8' ' N' COOH H OR ^CÜGH where each is a connection point and they are each independently from 0 to 10. [000251] In some forms, L comprises a structure of: Petition 870250096077, dated 10 / 21 / 2025, pp. 136 / 378 132 / 297 where each is a point of attachment and is from 1 to 32. In at least one exemplary embodiment, né is from 1 to 30ewéde0a5. [000252] In some forms, the linker comprises the structure of: Petition 870250096077, dated 10 / 21 / 2025, pp. 137 / 378 133 / 297 where 1 to 16 is each a point of attachment. [000253] In some forms, L comprises the structure of: where each is a fixation point, n is from 1 to 30 and w is from 0 to 5. [000254] In one embodiment, L is selected from the following list: Petition 870250096077, dated 10 / 21 / 2025, pp. 138 / 378 134 / 297 alkyl polyethylene glycol (PEG) polyproline (PEG) oligopiperidine oligo-(4-piperidine carboxylic acid) saccharopeptide Petition 870250096077, dated 10 / 21 / 2025, page 139 / 378 135 / 297 saccharopeptide where n is 0-30. [000255] Specific examples of exemplary conjugate compounds are provided here. Those skilled in the art will understand that the compound may exhibit polymorphism; the compound may comprise any racemic, optically active, polymorphic or stereoisomeric form, or mixtures thereof, of a compound exhibiting the useful properties described, being well known in Petition 870250096077, dated 10 / 21 / 2025, page 140 / 378 136 / 297 technique for preparing optically active forms (e.g., by resolution of the racemic form by recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase) and for determining antitumor activity using the standard tests described herein, or using other similar tests that are well known in the art. Furthermore, unless expressly stated otherwise, the structures described herein shall also include all stereochemical forms of the structure, i.e., the right-hand (R) and left-hand (S) configurations of each asymmetric center. Therefore, simple stereochemical isomers, as well as enantiomeric and diastereomeric mixtures of the present compound, are within the scope of this disclosure. [000256] The specific values ​​listed here for radicals, substituents, and ranges are for illustrative purposes only, unless otherwise specified; such examples do not exclude other defined values ​​or other values ​​within defined ranges for the radicals and substituents. For example, (C1-C6)alkyl can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, 3-pentyl, or hexyl; (C1-C3)alkyl can be iodomethyl, bromomethyl, chloromethyl, fluoromethyl, trifluoromethyl, 2-chloroethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, or pentafluoroethyl; (C1-C3)alkoxy can be methoxy, ethoxy, or propoxy; and (C2-C6)alkanoyloxy can be acetoxy, propanoyloxy, butanoyloxy, isobutanoyloxy, pentanoyloxy, or hexanoyloxy. [000257] Furthermore, when a fraction is replaced by an R-substituted substituent or a substituted group, the group may be termed “R-substituted”. When a fraction is R-substituted or is otherwise described as generally comprising a substituted group, the fraction is replaced by at least one R-substituted substituent, and each substituent is Petition 870250096077, dated 10 / 21 / 2025, p. 141 / 378 137 / 297 optionally different. It should be noted that the substituted group (or substituent R) may comprise any molecule or combination of molecules, provided that its inclusion does not substantially affect the overall structure and shape of the compound, nor alter any hydrogen bonds essential for the underlying compound to achieve its intended purpose (e.g., binding to a targeted pattern recognition receptor). [000258] When substituent groups are specified by conventional chemical formulas, written from left to right, they equally encompass chemically identical substituents that would result from writing the structure from right to left, for example, —CH2O— is equivalent to —OCH2—. [000259] In some embodiments, a compound comprises a radical of a targeting fraction conjugated with a radical of an immune modulator or a pharmaceutically acceptable salt or hydrate thereof, such that the immune modulator (or radical thereof) or pharmaceutically acceptable salt or hydrate thereof remains pharmaceutically active when conjugated. The targeting fraction may comprise any targeting fraction described herein and, in at least one embodiment, comprises a folate ligand, any other folate receptor-binding molecule (e.g., or a functional fragment or analog of any of the foregoing) or a pyrido[2,3-d]pyrimidine analog. In some embodiments, the targeting fraction (or compound or radical thereof) is specific for FRp. [000260] In some embodiments, a compound comprises one or more ligands, wherein a radical of the targeting moiety is conjugated to a radical of the immune modulator by means of one or more ligands. For example, when the immune modulator or its salt or hydrate Petition 870250096077, dated 10 / 21 / 2025, p. 142 / 378 138 / 297 pharmaceutically acceptable has Formula I or II, a radical of the immune modulator may be conjugated to a radical of the targeting fraction in one of R1, R2, or R3, via a linker or directly. Similarly, when the pharmaceutically acceptable immune modulator or its salt or hydrate has Formula III, a radical of the immune modulator may be conjugated to a radical of the targeting fraction in one of R1 or R3, via a linker or directly. Alternatively, when the pharmaceutically acceptable immune modulator or its salt or hydrate has Formula IV, a radical of the immune modulator may be conjugated to a radical of the targeting fraction in one of R1 or R2 via a linker or directly. As described herein, a linker may be releasable or non-releasable. [000261] It is understood that any combination of a compound radical (e.g., a compound radical in any of Tables 1 or 2), a ligand (e.g., as provided herein), and a ligand radical (e.g., a ligand radical in any of Tables 3 to 6) may be combined to form a compound provided herein. In some embodiments, the compound radical or ligand radical is a carbon atom or heteroatom (e.g., O, S, N, etc.). In some embodiments, the compound radical is C or O. In some embodiments, the ligand radical is C or O. In some embodiments, the point of attachment of the compound and the ligand (e.g., via a ligand) is determined by the location of the radical. In some embodiments, the ligands comprise a spacer (e.g., as described elsewhere in this document).It is also understood that any compound given here can be synthesized in a process similar to that given in the methods provided in the Examples. Petition 870250096077, dated 10 / 21 / 2025, p. 143 / 378 139 / 297 [000262] Non-limiting examples of the compound given here are provided in Table 7. [000263] Table 7. Examples of Compounds. Compound Ligand A· ^^0 PX n 0 a· where n is from 1 to 16 A· A 1- F ΌΟΟΗ a· m is from 1 to 5 Z· '-^0 PX n 0 a· where n is from 1 to 16 Z· o . Γ mf An'Pooh H a· m is from 1 to 5 F· X° n 0 a· where n is from 1 to 16 Petition 870250096077, dated 10 / 21 / 2025, p. 144 / 378 140 / 297 F· O 8^^0^ ΑΝΑθΟΟΗ H m is 1 to 5 a· L· \° in ( jue n is PA n 0 from 1 to 16 a· L· o ΡΡΛ if ΠΊ f AnAcoOH H m is 1 to 5 a· D· 8^-(4^0if rn f AnPíooh H m é 1 a 5 a· A· X° Pr b· Petition 870250096077, dated 10 / 21 / 2025, p. 145 / 378 141 / 297 where η is from 1 to 16 A· UI f· Vo' ' 0 where n is from 1 to 16 A· x° where n is n 0 from 1 to 16 h· A· \° where n is hM n 0 from 1 to 16 aa· A· \° where n is n 0 from 1 to 16 bb· A· \° where n is -A n 0 from 1 to 16 cc· A· \° where n is n 0 from 1 to 16 aaa· Petition 870250096077, dated 10 / 21 / 2025, page 146 / 378 142 / 297 ζ· \° in ^ue η is from 1 to 16 b· ζ· χ° in ^ue η is ρρ η 0 from 1 to 16 f· ζ· χ° in ^ue η is HP n 0 : from 1 to 16 h· ζ· \O in ^ue η is -pn 0 : from 1 to 16 aa· ζ· χ° in ^ue η is PP n 0 : from 1 to 16 bb· ζ· χ° in ^ue η is -P n 0 : from 1 to 16 cc· Petition 870250096077, dated 10 / 21 / 2025, page 147 / 378 143 / 297 z· \ n 0 where n is from 1 to 16 aaa· [000264] Non-limiting examples of compounds given here are provided in Table 8. [000265] Table 8. Additional examples of compounds Petition 870250096077, dated 10 / 21 / 2025, pp. 148 / 378 144 / 297 Petition 870250096077, dated 10 / 21 / 2025, p. 149 / 378 145 / 297 Petition 870250096077, dated 10 / 21 / 2025, p. 150 / 378 146 / 297 Petition 870250096077, dated 10 / 21 / 2025, pp. 151 / 378 147 / 297 Petition 870250096077, dated 10 / 21 / 2025, p. 152 / 378 148 / 297 [000266] In some cases, a conjugated compound provided here has the structure of Formula XIV (for example, either a functional fragment or analogue thereof, which includes the TLR7 agonist of Formula III conjugated with a folate via a releasable ligand): Petition 870250096077, dated 10 / 21 / 2025, pp. 153 / 378 149 / 297 (XIV} or is a pharmaceutically acceptable salt or hydrate thereof. [000267] In another embodiment, a conjugated compound provided herein has the structure of Formula XV (for example, or a functional fragment or analogue thereof, which includes the TLR7 agonist of Formula II conjugated with a folate via a releasable ligand (for example, Compound 3B)): (XV) or is a pharmaceutically acceptable salt or hydrate thereof. [000268] In another embodiment, a conjugated compound provided herein has the structure of Formula XVI (for example, or a functional fragment or analogue thereof, which includes the TLR7 agonist of Formula II) Petition 870250096077, dated 10 / 21 / 2025, page 154 / 378 150 / 297 conjugated with a folate via a non-releasable ligand comprising three PEGs (e.g., Compound 3D)): (XVI) or is a pharmaceutically acceptable salt or hydrate thereof. [000269] In yet another embodiment, a conjugated compound provided herein has the structure of Formula XVII (for example, or a functional fragment or analogue thereof, which includes the TLR7 agonist of Formula II conjugated with a folate by means of a non-releasable ligand comprising twelve PEGs (for example, Compound 3C)): Petition 870250096077, dated 10 / 21 / 2025, page 155 / 378 151 / 297 min is either a pharmaceutically acceptable salt or hydrate thereof. [000270] Other embodiments of a conjugated compound provided herein have the structure of Formula XVIII (e.g., either a functional fragment or analogue thereof, which includes the TLR7 agonist of Formula II conjugated with a folate via a non-releasable ligand comprising sixteen PEGs (e.g., Compound 3D')): (XVIII} Petition 870250096077, dated 10 / 21 / 2025, pp. 156 / 378 152 / 297 is either a pharmaceutically acceptable salt or hydrate thereof. [000271] Other embodiments of a conjugated compound provided herein have the structure of Formula XIX (for example, either a functional fragment or analogue thereof, which includes the TLR7 agonist of Formula III conjugated with a folate (Compound 1B)): [000272] In some embodiments, folate-conjugated TLR-7 / 8 agonists provide specificity for a diseased cell type. In one embodiment, the folate-TLR7 / 8 agonist compound can be administered (e.g., specifically) into the endosome of FRp+ macrophages, for example, limiting the system's exposure to TLR-7 / 8 agonists. [000273] One embodiment provides a compound represented by the structure of Formula (2-1): or a pharmaceutically acceptable salt or carbohydrate thereof, Petition 870250096077, dated 10 / 21 / 2025, pp. 157 / 378 153 / 297 in which, in Formula (2-1): R1, R3, R4 and R5 are each independently an H, an alkyl, an alkoxy, an alkenyl, an alkynyl, an alicyclic, an aryl, an biaryl, halo, heteroaryl, -C0R2x, (n= 0-30) R2 is an H, -OH, -NH2, -NHR2x, N3, -NH-CH2-NH2, -CONH2, -SO2NH2, -NH-CS-NH2, R2* Y is an H, -OH, -NH2, -NHR2x, -O-R2x, -SO-R2x, -SH, -SO3H, -N3, -CHO, -COOH, -CONH2, -COSH, -COR2x, -SO2NH2, alkenyl, alkynyl, alkoxyl, -NH-CH2-NH2, -CONH2, -SO2NH2, -NH-CS-NH2, Each of R2x and R2y is independently selected from the group consisting of H, -OH, -CH2-OH, -NH2, -CH2-NH2, -COOMe, COOH, -CONH2, -COCH3, alkyl, alkenyl, alkynyl, alicyclic, aryl, biaryl and heteroaryl, and each R2z is independently selected from the group consisting of -NH2, -NR2qR2q', -O-R2q, -SO-R2q and -COR2q; where each of R2q and R2q' is independently alkyl or H; and Petition 870250096077, dated 10 / 21 / 2025, pp. 158 / 378 154 / 297 is a non-aromatic, monocyclic or bicyclic heterocycle containing 3 to 10 N members; wherein, in Formula (2-1), each of X1, X2 and X3 is independently CRq or N, and each Rq is independently H, halogen or an optionally substituted alkyl; and wherein, in Formula (2-1), n ​​is 0-30 and in is 0-4. [000274] Another embodiment provides a compound having the structure of Formula (2-IA): Formula (2-IA) where: Rl is an optionally substituted C3-C8 alkyl (e.g., acyclic or cyclic) (e.g., optionally substituted by one or more substituents, each substituent independently being a halogen, alkyl, heteroalkyl, alkoxy, or cycloalkyl); R2 is H, -ORz, -SO2N(Rz)2, -NR2xR2y or N3; Y is H, -ORz, -NR2xR2y, -SRz, -SORz, -SO3Rz, -N3, -CORz, COORz, -CON(Rz)2, -COSRz, -SO2N(Rz)2 or -CON(Rz)2; Petition 870250096077, dated 10 / 21 / 2025, pp. 159 / 378 155 / 297 R2x and R2y are each independently hydrogen, N(Rz)2, -CON(Rz)2, -C(Rz)2-N(Rz)2, -CS-N(Rz)2 or optionally substituted alkyl (for example, optionally substituted by one or more substituents, each substituent being independently oxo, halogen, alkyl, heteroalkyl, alkoxy or cycloalkyl); each Rz is independently hydrogen, halogen or optionally substituted alkyl; or R2x and R2y are taken together to form an optionally substituted heterocycloalkyl (for example, where the optionally substituted heterocycloalkyl is a mono- or bicyclic heterocycloalkyl and / or where the optionally substituted heterocycloalkyl is a 3- to 10-membered heterocycloalkyl); each R3 is independently a halogen, -N3, -CN, NO2, -CORz, -COORz, -CON(Rz)2, -COSRz, -SO2N(Rz)2, -CON(Rz)2, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino, hydroxyl or thiol, wherein alkyl, alkoxy, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted; R4 and R5 are each independently alkyl, alkoxy, halogen or cycloalkyl, wherein the alkyl, alkoxy and cycloalkyl are optionally substituted; en is 1-6 en is 0-4, or a pharmaceutically acceptable salt or hydrate thereof. [000275] At least one embodiment provides a compound, or a pharmaceutically acceptable salt or hydrate thereof, having the structure of Formula (2-I) or (2-IA), where n is 1-30. In one embodiment, n is 1-6. In another embodiment, n is 1-3. In another embodiment, n is 1 or 2. In another embodiment, n is 0. In another embodiment, n is 1. In another Petition 870250096077, dated 10 / 21 / 2025, pp. 160 / 378 156 / 297 embodiment, n is 1 and Y is -OH. In another embodiment, n is 1 and Y is -NH2. In one embodiment, the compound is represented by the structure of Toll-tike receptor (TLR) 7 (TLR7)-1 (Compound 1). In one embodiment, the compound is represented by the structure of TLR7-1 (Compound 2). In one embodiment, the compound is represented by the structure of TLR7-1 (Compound 3). The structures of such compounds are illustrated in FIG. 1C. [000276] At least one embodiment provides a compound, or a pharmaceutically acceptable salt or hydrate thereof, having the structure of Formula (2-1) or (2-IA) where Y is -OH, OCH3, -NH2, NHNH2, -NHCONH2, -SH, -SO2NH2, -N3, -COOH, -COCH3, -COOCH3 or -CONH. [000277] At least one embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (2-1) or (2-IA) where Y is an H, -NH2, -NHR2x, -O-R2X, -SOR2x, -SH, -SO3H, -N3, -CHO, -COOH, -CONH2, -COSH, -COR2x, SO2NH2, alkenyl, alkynyl, alkoxyl, -NH-CH2-NH2, -CONH2, -SO2NH2, NH-CS-NH2, THE R^ [000278] One embodiment provides a compound, or a pharmaceutically acceptable salt or hydrate thereof, having the structure of Formula (2-1) or (2-IA) where Y is OH. [000279] At least one embodiment provides a pharmaceutically acceptable compound, or salt or hydrate thereof, having the structure of Formula (2-1) or (2-IA) where Y is NH2. [000280] At least one embodiment provides a pharmaceutically acceptable compound, or salt or hydrate thereof, having the structure of Formula (2-1) or (2-IA) where n is 1 and Y is OH. Petition 870250096077, dated 10 / 21 / 2025, pp. 161 / 378 151 / 291 [000281] At least one embodiment provides a pharmaceutically acceptable compound, or salt or hydrate thereof, having the structure of Formula (2-I) or (2-IA) where n is 1 and Y is NH2. [000282] At least one embodiment provides a pharmaceutically acceptable compound, or salt or hydrate thereof, having the structure of Formula (2-1) or (2-IA), where n is O and Y is NH2. [000283] At least one embodiment provides a compound, or a pharmaceutically acceptable salt or hydrate thereof, having the structure of Formula (2-1) or (2-IA), wherein R1 is an optionally substituted alkyl. In one embodiment, R1 is an optionally substituted C3-C6 alkyl. In another embodiment, R1 is an optionally substituted acyclic C3-C6 alkyl. In another embodiment, RI is butyl. [000284] At least one embodiment provides a compound, or a pharmaceutically acceptable salt or hydrate thereof, having the structure of Formula (2-I) or (2-IA), wherein R2 is -NR2xR2y. In one embodiment, R2 is NH2. [000285] At least one embodiment provides a pharmaceutically acceptable compound, or salt or hydrate thereof, having the structure of Formula (2-I) or (2-IA) where R3 is H. [000286] One embodiment provides a compound, or a pharmaceutically acceptable salt or hydrate thereof, having the structure of Formula (2I) or (2-IA) wherein R4 is alkyl. In one embodiment, R4 is methyl. [000287] At least one embodiment provides a compound, or a pharmaceutically acceptable salt or hydrate thereof, having the structure of Formula (2-I) or (2-IA) wherein R5 is alkyl. In one embodiment, R5 is methyl. [000288] At least one embodiment provides a compound, or a pharmaceutically acceptable salt or hydrate thereof, having the structure of Formula (2-I) or (2-IA) wherein R4 and R5 are each alkyl. In a Petition 870250096077, dated 10 / 21 / 2025, pp. 162 / 378 158 / 297 modality, R4 and R5 are each methyl. [000289] At least one embodiment provides a compound, or a pharmaceutically acceptable salt or hydrate thereof, having the structure of Formula (2-I) or (2-IA) wherein m is 0. In another embodiment, m is 1. In another embodiment, m is 2. In another embodiment, m is 3. In another embodiment, m is 4. [000290] At least one embodiment provides a compound, or a pharmaceutically acceptable salt or hydrate thereof, having the structure of Formula (2-I) wherein X1, X2 and X3 are each N. In one embodiment, X1 is N. In another embodiment, X2 is N. In another embodiment, X3 is N. [000291] At least one embodiment provides a pharmaceutically acceptable compound, or salt or hydrate thereof, having the structure of Formula (2-I) with the condition that compounds where n is 0 are excluded. [000292] At least one embodiment provides a pharmaceutically acceptable compound, or salt or hydrate thereof, having the structure of Formula (2-1) with the condition that compounds where n is 0 and Y is OH are excluded. [000293] At least one embodiment provides a pharmaceutically acceptable compound, or salt or hydrate thereof, having the structure of Formula (2-1) with the condition that compounds where n is 0, Y is OH, R1 is butyl, R2 is NH2, R3 is H and R4 and R5 are each methyl are excluded. [000294] At least one embodiment provides a compound, or a pharmaceutically acceptable salt or hydrate thereof, having the structure of Formula (2-I), provided that compound TLR7-1 is excluded. [000295] In some embodiments, the compound is represented by any one or more of the following formulas: Petition 870250096077, dated 10 / 21 / 2025, pp. 163 / 378 159 / 297 It is either a pharmaceutically acceptable salt or hydrate of any of the above structures, where: RI is an optionally substituted C3-C8 alkyl (e.g., acyclic or cyclic) (e.g., optionally substituted by one or more substituents, each substituent independently being a halogen, alkyl, heteroalkyl, alkoxy, or cycloalkyl); R2 is H, -ORz, -SO2N(Rz)2, -NR2xR2y or N3; Y is a binding site for the ligand or targeting ligand of the compound (e.g., of the first therapy or first drug in this document) and comprises H, -ORz, NR2xR2y, -SRz, -SORz, -SO3Rz, -N3, -CORz, -COORz, -CON(Rz)2, COSRz, -SO2N(Rz)2 or -CON(Rz)2; R2x and R2y are each independently hydrogen, Petition 870250096077, dated 10 / 21 / 2025, p. 164 / 378 160 / 297 N(Rz)2, -CON(Rz)2, -C(Rz)2-N(Rz)2, -CS-N(Rz)2 or optionally substituted alkyl (for example, optionally substituted by one or more substituents, each substituent being independently oxo, halogen, alkyl, heteroalkyl, alkoxy or cycloalkyl); each Rz is independently hydrogen, halogen or optionally substituted alkyl; or R2x and R2y are taken together to form an optionally substituted heterocycloalkyl (for example, where the optionally substituted heterocycloalkyl is a mono- or bicyclic heterocycloalkyl and / or where the optionally substituted heterocycloalkyl is a 3- to 10-membered heterocycloalkyl); each R3 is independently a halogen, -N3, -CN, NO2, -CORz, -COORz, -CON(Rz)2, -COSRz, -SO2N(Rz)2, -CON(Rz)2, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino, hydroxyl or thiol, wherein alkyl, alkoxy, heteroalkyl, cycloalkyl or heterocycloalkyl is optionally substituted; R4 and R5 are each independently alkyl, alkoxy, halogen, or cycloalkyl, wherein the alkyl, alkoxy, and cycloalkyl are optionally substituted; en is 1-6 and en is 0-4. [000296] In some embodiments, the compound is represented by any one or more of the following formulas: Petition 870250096077, dated 10 / 21 / 2025, pp. 165 / 378 161 / 297 or a pharmaceutically acceptable salt or carbohydrate thereof. [000297] In some forms, the compound is represented by one or more of the following formulas: Petition 870250096077, dated 10 / 21 / 2025, pp. 166 / 378 162 / 297 Petition 870250096077, dated 10 / 21 / 2025, pp. 167 / 378 163 / 297 [000298] As noted above, this disclosure also refers to compounds (e.g., their radicals) (e.g., TLR 7 and / or 8 agonists (TLR7 / 8)) that are conjugated, directly or via a ligand, to a targeting moiety (e.g., their radicals) that targets a pattern recognition receptor or DAMP of a cell. In some embodiments, the targeting ligand comprises a folate ligand or a functional fragment or analog thereof, e.g., pteroyl amino acids. In some embodiments, the ligands are non-releasable. In some embodiments, the compound provides targeting molecules (e.g., their radicals) with non-releasable ligands, thus reducing systemic exposure to TLR7 / 8 agonists. In some embodiments, the compound provides targeting molecules (e.g., their radicals) with non-releasable ligands, thus reducing the systemic adverse effects of TLR7 / 8 agonists. [000299] One embodiment provides a compound, or a pharmaceutically acceptable salt or hydrate thereof, having the structure: Petition 870250096077, dated 10 / 21 / 2025, pp. 168 / 378 164 / 297 Petition 870250096077, dated 10 / 21 / 2025, pp. 169 / 378 165 / 297 Petition 870250096077, dated 10 / 21 / 2025, pp. 170 / 378 166 / 297 Petition 870250096077, dated 10 / 21 / 2025, pp. 171 / 378 167 / 297 Petition 870250096077, dated 10 / 21 / 2025, pp. 172 / 378 168 / 297 NH^ [000300] One embodiment provides a compound, or a pharmaceutically acceptable salt or hydrate thereof, having the structure: Petition 870250096077, dated 10 / 21 / 2025, pp. 173 / 378 169 / 297 Petition 870250096077, dated 10 / 21 / 2025, pp. 174 / 378 170 / 297 Hí / k αΐ £ ι Η 1Λγΰο QX ? 1? Ο \ ί ίΓ 'ΜΗ ΥΖΎ Sri Petition 870250096077, dated 10 / 21 / 2025, pp. 175 / 378 171 / 297 It 1 1 U VA 0 1 NK, o 2 * NH 7 oV __11___ NH H 0 HN^-rí Λ Λ JHH^NNN 3 ô .aoh z S >. NH:A .NH 7 V12ov0H r _ U J. NH ο ΓΑΤ^^η,,^^ιί toóv 4 0 Petition 870250096077, dated 10 / 21 / 2025, pp. 176 / 378 172 / 297 Petition 870250096077, dated 10 / 21 / 2025, pp. 177 / 378 173 / 297 [000301] The compounds can be prepared by conventional organic synthesis methods practiced by experts in the field. The general reaction sequences described below represent a useful general method for the preparation of the compounds and are not intended to be limiting in scope or usefulness. [000302] The descriptions of compounds are limited by the principles of chemical bonding known to experts in the field. Consequently, when a group can be replaced by one or more substituents, such substitutions are selected in order to obey the principles of chemical bonding and to generate compounds that do not Petition 870250096077, dated 10 / 21 / 2025, pp. 178 / 378 174 / 297 are inherently unstable and / or would be known by a specialist in the field as likely to be unstable under ambient conditions, such as aqueous, neutral and various known physiological conditions. For example, a heterocycloalkyl or heteroaryl is linked to the rest of the molecule via a heteroatom in the ring, in accordance with the principles of chemical bonding known to specialists in the field, thus avoiding inherently unstable compounds.[000303] The terms “'identical'” or “percent identity”, in the context of two or more polypeptide sequences, refer to two or more sequences or subsequences that are identical or have a specified percentage of peptides that are identical (i.e., about 60% identity, preferably 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater identity in a specified region when compared and aligned for maximum match in a comparison window or designated region, such as a targeting end, folate end, linker or warhead) as measured using sequence comparison algorithms known in the art or by manual alignment and visual inspection. Such sequences are then considered “substantially identical”.In other words, identity exists in one or more regions of the overall sequence, provided that the overall shape and structure of the molecule, and the hydrogen bond(s), when appropriate, are maintained in such a way that it fits substantially into the target binding site and functions as an agonist of the same. [000304] Compounds may be administered in unit dose forms and / or compositions containing one or more pharmaceutically acceptable carriers, adjuvants, diluents, excipients and / or vehicles, and combinations thereof. The term “administration” and its derivatives generally refer to any and all means of introduction. Petition 870250096077, dated 10 / 21 / 2025, pp. 179 / 378 175 / 297 of the compounds described herein to the host subject, including, but not limited to, oral, intravenous, intramuscular, subcutaneous, transdermal, inhalation, buccal, ocular, sublingual, vaginal, rectal and similar routes of administration. [000305] Salts and Carbohydrates [000306] Compounds (for example, conjugates or parts thereof) may be presented as a pharmaceutically acceptable salt. A “pharmaceutically acceptable salt” of a compound refers to salts whose counter-ions can be used in pharmaceutical products. Such salts include (i) acid addition salts, which can be obtained by reacting the free base of the original compound with inorganic acids, such as hydrochloric acid and hydrobromic acid.nitric acid, phosphoric acid, sulfuric acid, perchloric acid and the like, or with organic acids, such as acetic acid, oxalic acid, malic acid (D) or (L), maleic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, succinic acid, malonic acid and the like, and (ii) salts formed when an acidic proton present in the original compound is replaced by a metal ion, for example, an alkali metal ion, an alkaline earth ion or an aluminum ion, or coordinates with an organic base, such as ethanolamine, diethanolamine, triethanolamine, trimethanine, N-methylglucamine and the like. Pharmaceutically acceptable salts are well known to those skilled in the art, and any pharmaceutically acceptable salt of this type is contemplated herein. [000307] In several forms, suitable basic salts are formed from bases that form non-toxic salts. Illustrative examples include arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, and zinc salts. Hemisals of acids and bases can also be formed, by Petition 870250096077, dated 10 / 21 / 2025, pp. 180 / 378 176 / 297 example, hemisulfate and hemicalcium salts. [000308] In some embodiments, the pharmaceutically acceptable salt is selected from hydrobromide, citrate, trifluoroacetate, ascorbate, hydrochloride, tartrate, triflate, maleate, mesylate, formate, acetate or fumarate. [000309] Pharmaceutically acceptable salts can be synthesized from the original compound containing a basic or acidic moiety by complementary chemical methods. In some cases, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pennsylvania, 1985, the description of which is incorporated herein by reference. [000310] The compound, or its pharmaceutically acceptable salt, may exist in undissolved forms as well as in solvated forms, including hydrated forms. Solvated forms may be equivalent to non-solvated forms. In each embodiment described herein, it should be understood that the formulas include and represent not only all pharmaceutically acceptable salts of the compounds, but also include any and all hydrates and / or solvates of the formulas of the compounds or their salts. The term “solvate” means a compound, or a salt thereof, which further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate. [000311] Certain functional groups, such as hydroxyl, amino, and similar groups, can form coordination complexes and / or conjugates with water and / or Petition 870250096077, dated 10 / 21 / 2025, pp. 181 / 378 177 / 297 various solvents. Consequently, the formulas should be understood as including and representing these various hydrates and / or solvates. Non-hydrates and / or non-solvents of the bispecific adapters are also included. [000312] Pharmaceutical Compositions [000313] In view of the foregoing, a composition (e.g., a pharmaceutical composition) for the treatment of cancer is also provided, comprising at least one compound of the present invention and a pharmaceutically acceptable carrier or excipient. The term “composition” generally refers to any product comprising more than one ingredient, including the compounds described herein. “Pharmaceutically acceptable carrier” includes any of the standard pharmaceutical carriers, such as, but not limited to, a buffering agent, a preservative agent, an anesthetic agent, a solubilizing agent, an isotonic agent, a humectant, and a stabilizer. The term also encompasses any of the agents approved by a regulatory agency, such as the U.S. Food and Drug Administration, or listed in the U.S. Pharmacopoeia for use in animals (e.g., mammals, such as humans).The carrier can be a phosphate-buffered saline solution, water, or an emulsion, such as an oil / water or water / oil emulsion. [000314] It should be understood that the compositions can be prepared from isolated compounds described herein or from salts, solutions, hydrates, solvates, and other forms of the compounds. It is important to emphasize that certain functional groups, such as hydroxyl, amino, and similar groups, can form complexes with water and / or various solvents, in the various physical forms of the compounds. It should also be understood that the compositions can be prepared from various amorphous, non-amorphous, partially crystalline, crystalline, and / or other morphological forms of the compounds. Petition 870250096077, dated 10 / 21 / 2025, pp. 182 / 378 178 / 297 compounds described herein, and the compositions may be prepared from various hydrates and / or solvates of the compounds described herein. Consequently, pharmaceutical compositions that cite the compounds include each, or any combination, or individual forms of the various morphological forms and / or solvate or hydrate forms of the compounds described herein. [000315] Compounds can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient, in a variety of forms adapted to the chosen route of administration. For example, the pharmaceutical composition can be formulated and administered orally or parenterally, intravenously, intra-arterially, intraperitoneally, intrathecally, epidurally, intracerebroventricularly, intraurethrally, intrasternally, intracranially, intratumorally, intramuscularly, topically, by inhalation, and / or subcutaneously. In fact, in at least one embodiment, a compound and / or composition as described herein can be administered directly into the bloodstream, muscle, or internal organ. [000316] For example, in at least one embodiment, the compounds may be administered systemically (orally, for example) in combination with a pharmaceutically acceptable vehicle, such as an inert diluent or an assimilable edible carrier. For oral therapeutic administration, the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, scouring pads, capsules, elixirs, suspensions, syrups, wafers and the like. The percentage of the compositions and preparations may vary and may be between about 1% and about 99% by weight of the active ingredient(s) and a binder, excipients, a disintegrating agent, a lubricant and / or a sweetening agent (as known in the art). The amount of active compound in such Petition 870250096077, dated 10 / 21 / 2025, pp. 183 / 378 179 / 297 therapeutically useful compositions is such that an effective dosage level will be obtained. [000317] The preparation of parenteral compounds / compositions under sterile conditions, for example by lyophilization, can be easily performed using standard pharmaceutical techniques well known to those skilled in the art. In at least one embodiment, the solubility of a compound used in the preparation of a parenteral composition can be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents. [000318] As noted previously, the compounds / compositions can also be administered by infusion or injection (e.g., using needle injectors (including microneedles) and / or needleless injectors). Solutions of the active composition may be aqueous, optionally mixed with a non-toxic surfactant and / or may contain carriers or excipients such as salts, carbohydrates and buffering agents (preferably at pH 3 to 9), but for some applications they may be more suitablely formulated as a sterile non-aqueous solution or as a dry form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water or phosphate-buffered saline (PBS). For example, dispersions may be prepared in glycerol, liquid PEGs, triacetin and mixtures thereof, and in oils. Under normal storage and use conditions, these preparations may also contain a preservative to prevent the growth of microorganisms. [000319] Pharmaceutical forms suitable for injection or infusion may include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredients which are adapted for the extemporaneous preparation of injectable solutions or dispersions or Petition 870250096077, dated 10 / 21 / 2025, pp. 184 / 378 180 / 297 sterile infusible tablets, optionally encapsulated in liposomes. In all cases, the final pharmaceutical form must be sterile, flowable, and stable under manufacturing and storage conditions. The liquid vehicle or carrier may be a solvent or liquid dispersion medium comprising, for example, and without limitation, water, ethanol, a polyol (e.g., glycerol, propylene glycol, liquid PEG(s) and the like), vegetable oils, non-toxic glyceryl esters, and / or suitable mixtures thereof. In at least one embodiment, adequate flowability may be maintained by liposome formation, by maintaining the required particle size in the case of dispersions, or by the use of surfactants. The action of microorganisms may be prevented by the addition of various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In certain cases, it will be desirable to include one or more isotonic agents, such as sugars, buffers, or sodium chloride.Prolonged absorption of injectable compositions can be achieved by incorporating agents formulated to delay absorption, for example, aluminum monostearate and gelatin. [000320] Sterile injectable solutions can be prepared by incorporating the active compound and / or composition in the required amount of appropriate solvent with one or more of the other ingredients mentioned above, as needed, followed by sterilization by filtration. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred preparation methods are vacuum drying and lyophilization techniques, which produce a powder of the active ingredient plus any desired additional ingredient present in the previously filtered sterile solutions. [000321] For topical administration, it may be desirable to administer the present compounds to the skin as compositions or formulations in combination with a dermatologically acceptable carrier, which may Petition 870250096077, dated 10 / 21 / 2025, pp. 185 / 378 181 / 297 can be a solid or a liquid. For example, in certain embodiments, solid carriers may include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina, and the like. Similarly, useful liquid carriers may comprise water, alcohols, or glycols, or water-alcohol / glycol mixtures, in which the compounds present can be dissolved or dispersed to effective levels, optionally with the aid of non-toxic surfactants. Additionally or alternatively, adjuvants such as fragrances and antimicrobial agents may be added to optimize the properties for a particular use. The resulting liquid compositions can be applied from absorbent pads, used to impregnate bandages and / or other dressings, sprayed onto the target area using pump or aerosol sprayers, or simply applied directly to the desired area of ​​the individual. [000322] Thickeners such as synthetic polymers, fatty acids, salts and esters of fatty acids, fatty alcohols, modified celluloses or modified mineral materials can also be used with liquid carriers to form pastes, gels, ointments, soaps and the like for direct application to the skin. [000323] The terms “therapeutically effective,” “therapeutically effective dose,” “therapeutically effective amount,” “prophylactically effective amount,” or “prophylactically effective dose” mean (unless specifically indicated otherwise) an amount of a compound that, when administered once or over a course of treatment, affects the health, well-being, or mortality of an individual (for example, and without limitation, delays the onset and / or reduces the severity of one or more symptoms associated with cancer). Useful dosages of compounds can be determined by comparing their in vitro activity and in vivo activity in animal models. Methods of Petition 870250096077, dated 10 / 21 / 2025, pp. 186 / 378 182 / 297 Extrapolation of effective dosages in mice and other animals to human subjects is known in the art. In fact, the dosage of the compound may vary significantly depending on the condition of the host individual, the type of cancer to be treated, the degree of advancement of the pathology, the route of administration of the compound and tissue distribution, and the possibility of concomitant use of other therapeutic treatments (such as radiotherapy or additional medications in combination therapies). The amount of the composition required for use in treatment (e.g., the effective therapeutic or prophylactic amount or dose) will vary not only with the specific application but also with the salt selected (if applicable) and the characteristics of the individual (such as, for example, age, condition, sex, body surface area and / or mass of the individual, drug tolerance) and will ultimately be at the discretion of the attending physician, clinician, or other professional.Therapeutically effective or prophylactically effective amounts or doses may vary, for example, from about 0.05 mg / kg of patient body weight to about 30.0 mg / kg of patient body weight, or from about 0.01 mg / kg of patient body weight to about 5.0 mg / kg of patient body weight, including, but not limited to, 0.01 mg / kg, 0.02 mg / kg, 0.03 mg / kg, 0.04 mg / kg, 0.05 mg / kg, 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 1.0 mg / kg, 1.5 mg / kg, 2.0 mg / kg, 2.5 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, 4.5 mg / kg and 5.0 mg / kg. mg / kg, all of which are kg of patient body weight. All ranges specified in this paragraph include the indicated endpoints and all 0.05 g / m2 increments encompassed within each specified range. The total therapeutically or prophylactically effective amount of the compound may be administered in single or divided doses and may, at the physician's discretion, fall outside the typical range presented here. [000324] In another embodiment, the compound can be administered in Petition 870250096077, dated 10 / 21 / 2025, pp. 187 / 378 183 / 297 a therapeutically or prophylactically effective amount of about 0.5 g / m2 to about 500 mg / m2, from about 0.5 g / m2 to about 300 mg / m2, or from about 100 g / m2 to about 200 mg / m2. In other embodiments, the amounts may range from about 0.5 mg / m2 to about 500 mg / m2, from about 0.5 mg / m2 to about 300 mg / m2, from about 0.5 mg / m2 to about 200 mg / m2, from about 0.5 mg / m2 to about 100 mg / m2, from about 0.5 mg / m2 to about 50 mg / m2, from about 0.5 mg / m2 to about 600 mg / m2, from about 0.5 mg / m2 to about 6.0 mg / m2, from about 0.5 mg / m2 to about 4.0 mg / m2 or from about 0.5 mg / m2 to about 2.0 mg / m2. All ranges specified in this paragraph include the indicated endpoints and all 0.5 g / m2 increments within each specified range. The total amount may be administered in single or divided doses and may, at the physician's discretion, fall outside the typical range indicated here.These quantities are based on square meters of body surface area. [000325] In other embodiments, the amount of the compound (or pharmaceutically acceptable salt or hydrate thereof) to be administered to a subject may vary, for example, from about 50 nmol / kg to about 3,000 nmol / kg of the subject's body weight, about 50 nmol / kg to about 2,000 nmol / kg, about 50 nmol / kg to about 1,000 nmol / kg, about 50 nmol / kg to about 900 nmol / kg, about 50 nmol / kg to about 800 nmol / kg, about 50 nmol / kg to about 700 nmol / kg, about 50 nmol / kg to about 600 nmol / kg, about 50 nmol / kg to about 500 nmol / kg, about 50 nmol / kg to about 400 nmol / kg, about 50 nmol / kg to about 300 nmol / kg, about 50 nmol / kg to about 200 nmol / kg, about 50 nmol / kg to about 100 nmol / kg, about 100 nmol / kg to about 300 nmol / kg, about 100 nmol / kg to about 500 nmol / kg, about 100 nmol / kg to about 1,000 nmol / kg, or about 100 nmol / kg to about 2,000 nmol / kg of the subject's body weight. In Petition 870250096077, dated 10 / 21 / 2025, pp. 188 / 378 184 / 297 In other modalities, the dose may be approximately 100 nmol / kg, approximately 150 nmol / kg, approximately 200 nmol / kg, approximately 250 nmol / kg, approximately 300 nmol / kg, approximately 350 nmol / kg, approximately 400 nmol / kg, approximately 450 nmol / kg, approximately 500 nmol / kg, approximately 600 nmol / kg, approximately 700 nmol / kg, approximately 800 nmol / kg, approximately 900 nmol / kg, approximately 1,000 nmol / kg, approximately 2,000 nmol / kg, or approximately 3,000 nmol / kg of the subject's body weight. In other modalities, doses between approximately 20 ug / kg and approximately 3 mg / kg of the subject's body weight may be administered. The amount may vary from about 0.2 mg / kg to about 0.4 mg / kg of the subject's body weight, or about 50 pg / kg of the subject's body weight. All ranges specified in this paragraph include the indicated endpoints and all increments of 1 nmol / kg or 10 pg / kg, as applicable, covered within each specified range. [000326] In some embodiments, in connection with measuring the expression of certain biomarkers and / or analyzing cytokine levels in a subject sample, what matters in this disclosure is not the specific methods used to detect the marker or set of markers, but rather what the markers are used to detect. There are many methods that can be used to detect the expression, quantification, or profiling of one or more biomarkers. Once the marker or set of markers to be detected or quantified has been identified, any of the various techniques (that are currently known or subsequently developed) can be used, with the provision of appropriate reagents.An expert in the field, when given one or more biomarkers to be identified, will be able to select the appropriate assay (e.g., a PCR-based assay or microassay for nucleic acid markers, an enzyme-linked immunosorbent assay (ELISA), protein or antibody microarray, or similar immunoassay, etc.) to perform the methods described herein. Petition 870250096077, dated 10 / 21 / 2025, pp. 189 / 378 185 / 297 published. [000327] Combinations [000328] A combination of a first therapy comprising any of the compounds or pharmaceutical compositions described herein and a second therapy comprising one or more checkpoint inhibitors is also provided. [000329] The second therapy may comprise one or more immune checkpoint inhibitors that can bind to and / or antagonize an immune checkpoint molecule. An “immune checkpoint inhibitor” or “antagonist” (as used in this context) is a molecule that inhibits, reduces, or blocks the activity of an immune checkpoint molecule to inhibit a suppressive effect that the immune checkpoint molecule has on the immune system. The inhibitor or antagonist may bind directly to the immune checkpoint molecule or to a ligand of the immune checkpoint molecule that mediates the activity of the immune checkpoint molecule. [000330] An agent that selectively binds to an immune checkpoint molecule, without limitation, may be, for example, an antibody or its antigen-binding fragment (including a humanized antibody or its antigen-binding fragment), a protein or a peptide, a small molecule, or a nucleic acid. An immune checkpoint molecule that is a nucleic acid may be, for example, an antisense molecule, a single- or double-stranded DNA oligonucleotide, a single- or double-stranded RNA oligonucleotide, a peptide nucleic acid (PNA), a single- or double-stranded RNAi molecule, a shRNA, or a siRNA. A small molecule is an organic compound. An agent that selectively binds to an immune checkpoint molecule may bind to nucleic acids or Petition 870250096077, dated 10 / 21 / 2025, pp. 190 / 378 186 / 297 amino acids of the immune checkpoint molecule sequence. An agent that selectively binds to an immune checkpoint molecule can bind to any region of the immune checkpoint molecule. [000331] A checkpoint inhibitor may comprise a small molecule or other agent that disrupts an immune checkpoint of a subject cell, such as, for example, programmed death 1 (PD-1), programmed death ligand 1 (PD-L1), cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), V domain lg T cell activation suppressor (VISTA), lymphocyte activator 3 (LAG3), T cell immunoglobulin-containing mucin domain protein 3 (TIM3), T cell immunoreceptor with lg and ITIM domains (TIGIT), programmed death ligand 2 (PD-L2), indoleamine 2,3-deoxygenase (IDO), arginase-1 (AGR1), B7 family inhibitory ligand B7H3 (B7-H3), B7 family inhibitory ligand B7-H4 (B7-H4), 2B4 (cluster of differentiation 244), lymphocyte attenuator B and T (BTLA), adenosine A2A receptor (A2aR) and / or a member of the killer cell immunoglobulin-like receptor (KIR) family, such as KIRs and C-type lectin receptors,and signal transducer and activator of transcription (STAT3). Disclosure is not limited to targeting the aforementioned receptors for immune checkpoint blockade, and other checkpoint inhibitory molecules may be targeted by immune checkpoint inhibitors in a combination therapy with the compound(s) and / or composition(s) described herein. The activity of the immune checkpoint molecule is referred to as its suppressive effect on an immune checkpoint. An immune checkpoint inhibitor may reduce or block the activity of an immune checkpoint molecule. [000332] Immunological checkpoints refer to pathways Petition 870250096077, dated 10 / 21 / 2025, pp. 191 / 378 187 / 297 inhibitory molecules integrated into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues to minimize collateral tissue damage. Immune checkpoint molecules can be either stimulatory or inhibitory to an immune checkpoint. This disclosure and claims refer to inhibitory immune checkpoint molecules as “immune checkpoint molecules.” Preliminary clinical findings with agents that block immune checkpoint molecules (e.g., PD-1, PD-L1, or CTLA-4) suggest opportunities to enhance antitumor immunity with the potential to produce effective clinical responses.The combination of immune checkpoint blockade with immune checkpoint inhibitor(s) along with the administration of the compounds and / or compositions described herein may increase the effectiveness of treatment in an individual with cancer or cancer recurrence. [000333] An immune checkpoint inhibitor is a type of drug that blocks the signaling of immune checkpoint molecules produced by some types of immune system cells, such as T cells and some cancer cells. Immune checkpoint inhibitors, therefore, can cause immune checkpoint blockade. [000334] Immune checkpoint molecules (e.g., PD1) can help keep immune responses in check and can prevent T cells from killing cancer cells. When these molecules are blocked, the “brakes” on the immune system are released (immune system inhibition is reduced or blocked), and T cells can kill cancer cells more effectively. Examples of checkpoint proteins found on T cells or cancer cells include PD-1 / PD-L1 and CTLA-4. In some Petition 870250096077, dated 10 / 21 / 2025, pp. 192 / 378 In 188 / 297 embodiments, immune checkpoint molecules are proteins. In certain embodiments, immune checkpoint molecules are nucleic acids that encode proteins. In some embodiments, immune checkpoint inhibitors bind to and / or antagonize immune checkpoint molecules. In some embodiments, immune checkpoint inhibitors are used in combination with the compounds and / or compositions described herein to treat a subject with cancer. [000335] In certain embodiments, the checkpoint inhibitor(s) may be selected from the group consisting of pembrolizumab, nivolumab, ipilimumab, cemiplimab, atezolizumab, avelumab, durvalumab, pidilizumab, MEDI-0680 monoclonal antibody, REGN2810 monoclonal antibody or AMP-224 fusion protein targeting PD-1, ociperlimab, islelizumab, a combination of ociperlimab and islelizumab, BMS-936559 / MDX-1105, MPDL3280A / RG7446 / atezolizumab, MSB0010718C / avelumab or MEDI4736 / durvalumab. tiragolumab, zimberelimab, tremelimumab, relatlimab, monoclonal antibody IMP321, nivolumab, etigilimab, domvanalimab, tiragolumab (RG6058), vibostolimab, avelumab and durvalumab. [000336] In certain embodiments, the checkpoint inhibitor is a PD-1 antagonist or a PD-L1 antagonist. In certain embodiments, the checkpoint inhibitor is a CTLA-4 antagonist. In certain embodiments, the checkpoint inhibitor is a VISTA antagonist. In certain embodiments, the checkpoint inhibitor is a LAG3 antagonist. In certain embodiments, the checkpoint inhibitor is a TIM3 antagonist. In certain embodiments, the checkpoint inhibitor is a TIGIT antagonist. Petition 870250096077, dated 10 / 21 / 2025, pp. 193 / 378 189 / 297 [000337] The PD-1 antagonist can be, for example, an agent that binds to and antagonizes PD-1. In some embodiments, the agent that binds to and antagonizes PD-1 is a peptide that binds to PD-1. In some embodiments, the agent that binds to and antagonizes PD-1 is a humanized antibody that selectively binds to PD-1. In some embodiments, the humanized antibody that selectively binds to PD-1 is nivolumab, pembrolizumab, pidilizumab, MEDI-0680 monoclonal antibody, REGN2810 monoclonal antibody, or AMP-224 fusion protein that targets PD-1. In some embodiments, the humanized antibody that selectively binds to PD-1 is nivolumab, pembrolizumab, or pidilizumab. PD-1 antagonists can be ociperlimab, islelizumab, or a combination of ociperlimab and islelizumab. [000338] The PD-L1 antagonist may be, for example, an agent that binds to and antagonizes PD-L1. The agent that binds to and antagonizes PD-L1 may be, for example, a peptide that binds to PD-L1. In certain embodiments, the agent that binds to and antagonizes PD-L1 is a humanized antibody that selectively binds to PD-L1. The humanized antibody that selectively binds to PD-L1 may be BMS-936559 / MDX-1 105, MPDL3280A / RG7446 / atezolizumab, MSBOO107 l 8C / avelumab or MEDI4736 / durvalumab. The PD-L1 antagonist may be tiragolumab, atezolizumab, avelumab, durvalumab or zimberelimab. [000339] Examples of drugs that target PD-L1 include, but are not limited to, Atezolizumab, Avelumab, and Durvalumab. In certain embodiments, the checkpoint inhibitor is an antibody that targets CTLA-4, such as Ipilimumab. Additionally, the checkpoint inhibitor may comprise a checkpoint inhibitor that targets T-cell immunoglobulin and mucin domain-containing protein-3 (CD366 or TIM3), which is a transmembrane protein. In alternative embodiments, checkpoint inhibitors... Petition 870250096077, dated 10 / 21 / 2025, pp. 194 / 378 190 / 297 checkpoints comprise small molecules or other agents that disrupt the immune checkpoint that is exploited by cancer cells to escape cell-mediated targeting or other immune-mediated mechanisms. [000340] The CTLA-4 antagonist may be, for example, an agent that binds to and antagonizes CTLA-4. In some embodiments, the agent that binds to and antagonizes CTLA-4 is a peptide that binds to CTLA-4. In some embodiments, the agent that binds to and antagonizes CTLA-4 is a humanized antibody that selectively binds to CTLA-4. In some embodiments, the humanized antibody that selectively binds to the CTLA-4 inhibitor is ipilimumab or tremelimumab. In some embodiments, the CTLA-4 antagonist is (i) an antisense molecule directed against CD80, CD86 and / or CTLA-4, (ii) an adnectin directed against CD80, CD86 and / or CTLA-4, (iii) a single- or double-stranded RNAi inhibitor of CD80, CD86 and / or CTLA-4, or (iv) a small molecule inhibitor of CD80, CD86 or CTLA-4. [000341] The VISTA antagonist may be, for example, an agent that binds to and antagonizes VISTA. In some embodiments, the agent that binds to and antagonizes VISTA is a peptide. In certain embodiments, the agent that binds to and antagonizes VISTA is an inhibitory antibody directed against VISTA. In some embodiments, the agent that binds to and antagonizes VISTA is a humanized antibody. In some embodiments, the agent that binds to and antagonizes VISTA is (i) an antisense molecule directed against VISTA, (ii) an adnectin directed against VISTA, (iii) a single- or double-stranded RNAi inhibitor of VISTA, or (iv) a small molecule inhibitor of VISTA. [000342] The LAG3 antagonist can be, for example, an agent that binds to and antagonizes LAG3. In some embodiments, the agent that binds to and antagonizes LAG3 is a peptide that binds to LAG3. In some Petition 870250096077, dated 10 / 21 / 2025, pp. 195 / 378 In 191 / 297 embodiments, the agent that binds to and antagonizes LAG3 is a humanized antibody that selectively binds to LAG3. In some embodiments, the humanized antibody that selectively binds to LAG3 is relatlimab, or the monoclonal antibody IMP321. [000343] The TIM3 antagonist can be, for example, an agent that binds to and antagonizes TIM3. In some embodiments, the agent that binds to and antagonizes TIM3 is a peptide that binds to TIM3. In some embodiments, the agent that binds to and antagonizes TIM3 is a humanized antibody that selectively binds to TIM3. In some embodiments, the humanized antibody that selectively binds to TIM3 is INCAGN02390. [000344] The TIGIT antagonist may be, for example, an agent that binds to and antagonizes TIM3. In some embodiments, the agent that binds to and antagonizes TIM3 is a peptide that binds to TIM3. In some embodiments, the agent that binds to and antagonizes TIM3 is a humanized antibody that selectively binds to TIM3. In some embodiments, the humanized antibody that selectively binds to TIM3 is etigilimab, domvanalimab, tiragolumab (RG6058), or vibostolimab. [000345] As mentioned, immune checkpoint blockade can be used as a combination therapy with the compounds and compositions described herein. In certain approaches, administration of the compounds / compositions and immune checkpoint inhibitor therapy results in greater than additive inhibition of cancer growth. [000346] When multiple therapeutic agents and / or therapies are co-administered, dosages may be adjusted appropriately, as recognized in the relevant art. “Co-administration” and combination therapy are not limited to simultaneous administration, but also include treatment regimens in which one compound or composition is Petition 870250096077, dated 10 / 21 / 2025, pp. 196 / 378 192 / 297 administered at least once during a course of treatment that calls for the administration of immune checkpoint inhibitor therapy to an individual. In some embodiments, one or more immune checkpoint inhibitors of the second therapy are administered on a different day than the first therapy comprising the compound / composition. In some embodiments, the second therapy is administered on the same day as the first therapy. In some embodiments, the second therapy (i.e., one or more immune checkpoint inhibitors) is administered on a different day from the first therapy (i.e., the compound / composition described herein), but within one day, within five days, within one week, within eight days, within two weeks, within three weeks, within one month, within two months, or within three months of the administration of the first therapy to the subject. [000347] In some modalities, the second therapy immune checkpoint inhibitor(s) is / are administered intravenously or subcutaneously. [000348] In certain modalities, the combination can be used to treat cancer recurrence in an individual or resistance in an individual to immune checkpoint blockade therapy. In certain modalities, the combination can be used to treat cancer in an individual. [000349] Uses and Methods [000350] In addition to the compounds described herein, methods are also provided for providing treatment and / or prevention of cancer recurrence. In some embodiments, a method is provided herein for treating an oncological disease or disorder in an individual in need thereof, comprising administering to the individual any compound provided herein, or a pharmaceutically acceptable salt or hydrate thereof, or Petition 870250096077, dated 10 / 21 / 2025, pp. 197 / 378 193 / 297 a composition (for example, pharmaceutical) comprising any compound supplied herein, or a pharmaceutically acceptable salt thereof, such as a compound having the structure of any of Formulas I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XX, Formula XXX, Formula 2-1, Formula 2-11, Formula 2-III, Formula 2-IV, Formula 2-V or Formula 2-VI. [000351] In some embodiments, a method is provided here for treating an oncological disease or disorder in an individual in need thereof, comprising administering to the individual any compound provided herein, or a pharmaceutically acceptable salt or hydrate thereof, or a composition (e.g., pharmaceutical) comprising any compound provided herein, or a pharmaceutically acceptable salt or hydrate thereof, such as a compound having the structure of any of Formulas I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XL, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XX, Formula XXX, Formula 2-I, Formula 2-II, Formula 2-III, Formula 2-IV, Formula 2-V or Formula 2-VI. In some embodiments, the cancerous disease or disorder is cancer.In some modalities, the cancer is selected from bladder cancer, brain cancer, liver cancer, kidney cancer, skin cancer, thymus carcinoma, gastrointestinal stromal tumor (GIST), esophageal cancer, pancreatic cancer, and breast cancer. [000352] In some embodiments, a method is provided here for treating a cancer-related disease or disorder in an individual who needs it, comprising administering to the individual of Petition 870250096077, dated 10 / 21 / 2025, pp. 198 / 378 194 / 297 any compound supplied herein, or a pharmaceutically acceptable salt or hydrate thereof, or a composition (e.g., pharmaceutical) comprising any compound supplied herein, or a pharmaceutically acceptable salt or hydrate thereof, such as a compound having the structure of any of Formulas I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XX, Formula XXX, Formula 2-I, Formula 2-II, Formula 2-III, Formula 2-IV, Formula 2-V or Formula 2-VI. [000353] In at least one embodiment, a method is provided for treating a subject suffering from, or at risk of developing, a disease state, wherein the disease state comprises cancer (or recurrence thereof) and the method comprises contacting a cell of the subject with at least one compound. At least one compound may comprise any of the compounds described herein and, in at least one exemplary embodiment, comprises a specific targeting fraction for FRB. In some cases, contact with a cell may be achieved by administering at least one compound to the subject intravenously, orally, intramuscularly, intraperitoneally, topically, or by inhalation or any of the other administration modalities described herein.Additionally or alternatively, at least one compound may comprise a composition containing one or more pharmaceutically acceptable carriers, adjuvants, diluents, excipients and / or vehicles, or combinations thereof. The dosage of at least one compound administered may be modified as appropriate by the clinician; however, at least one compound is preferably dosed in an amount that is therapeutically effective or prophylactically effective and, in at least one instance. Petition 870250096077, dated 10 / 21 / 2025, pp. 199 / 378 195 / 297 modality, the dosage is in a range between 1 nmol / kg of the subject's body weight and 50 nmol / kg of the subject's body weight. [000354] In certain embodiments, a method is provided herein for treating or preventing the recurrence or relapse of a cancerous disease state, comprising contacting a cell with at least one compound comprising an immune modulator or pharmaceutically acceptable salt or hydrate thereof linked, via a ligand, to a folate ligand or functional fragment or analogue thereof, wherein the immune modulator or pharmaceutically acceptable salt thereof targets a pattern recognition receptor or a DAMP. [000355] In certain modalities, the method of treatment of a subject with cancer may comprise administering a first therapy to the subject, the first therapy comprising at least one compound or composition thereof, and administering a second therapy to the subject, the second therapy comprising one or more checkpoint inhibitors (i.e., one or more agents that bind to and / or antagonize PD-1, PD-L1, CTLA-4, VISTA, LAG3, TIM3, TIGIT, PD-L2, IDO, AGR1, B7-H3, B7-H4, 2B4, BTLA, A2aR and / or a member of the KIR family, such as KIRs and C-type lectin receptors, and STAT3). Disclosure is not limited to targeting the aforementioned receptors for immune checkpoint blockade, and other checkpoint inhibitory molecules may be targeted by immune checkpoint inhibitors in combination therapy with the compound(s) and / or composition(s) described herein. [000356] At least one compound of the first therapy of the method may comprise any compound, or a pharmaceutically acceptable salt or hydrate thereof, described, or a composition (e.g., pharmaceutical) comprising any compound supplied herein, or a pharmaceutically acceptable salt or hydrate thereof. Petition 870250096077, dated 10 / 21 / 2025, pp. 200 / 378 196 / 297 such as a compound having the structure of any of Formulas I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XIL, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XX, Formula XXX, Formula 2-1, Formula 2-11, Formula 2-III, Formula 2-IV, Formula 2-V or Formula 2-VI. In some embodiments, the immune modulator comprises a TLR 3, 7, 8, 9 or 7 / 8 agonist. [000357] In certain embodiments, at least one compound comprises a radical of an immunomodulator or a pharmaceutically acceptable salt or hydrate thereof linked, via a ligand, to a targeting ligand, such as, for example, a folate ligand or a functional fragment or analogue thereof. The immunomodulator or pharmaceutically acceptable salt or hydrate thereof may target a pattern recognition receptor. Similarly, the composition comprising at least one compound may comprise any of the pharmaceutical compositions described. In certain embodiments, the composition comprises at least one such compound and one or more pharmaceutically acceptable carriers, adjuvants, diluents, excipients and / or vehicles, or combinations thereof. [000358] In certain embodiments of the methods, the immunomodulator radical of the compound comprises a TLR 3, 7, 8, 9, or 7 / 8 agonist. In certain embodiments, at least one compound (e.g., from the first therapy) has the following formula: Petition 870250096077, dated 10 / 21 / 2025, pp. 201 / 378 197 / 297 or is a pharmaceutically acceptable salt or hydrate thereof. In certain embodiments, the immunomodulator radical of the first therapy comprises a TLR agonist of Formula X or XX, or is a pharmaceutically acceptable salt or hydrate of Formula X or XX: (XX) where, in Formulas X and XX: RI is -NH2 or -NH-Rlx, R2 is an H, an alkyl, an alkenyl, an alkynyl, an alicyclic, an aryl, a biaryl, a heteroaryl, -NH-R2X, -O-R2X, -S-R2X, or ......- / X and í- is a non-aromatic mono- or bicyclic heterocycle containing N of 3 to 10 members, wherein: In Formula X, R3 is -OH, -SH, -NH2, or -NH-R1X; Petition 870250096077, dated 10 / 21 / 2025, p. 202 / 378 198 / 297 in Formula XX, X is a CH or an N; and each of R1X, R2x and R2y is independently selected from the group consisting of an H, an alkyl, an alkenyl, an alkynyl, an allicyl, an aryl, a biaryl and a heteroaryl. [000359] At least one component of the first therapy may comprise: or be a pharmaceutically acceptable salt or hydrate thereof, wherein, in Formula 2-1: R1, R3, R4 and R5 are each independently a hydrogen (H), an alkyl, an alkoxyl, an alkenyl, an alkynyl, an alicyclic, an aryl, a biaryl, a halo, a heteroaryl, -COR2X, ΗΛΐΥ φ * 0-30) R2*f, or ; R2 is an H, -OH, -NH2, -NHR2X, N3, -NH-CH2-NH2, -CONH2, A'*1 -SO2NH2, -NH-CS-NH2, or ; Y is the point of attachment to the linking ligand and / or directing ligand of the conjugate and comprises an H, -OH, -NH2, -NHR2X, Petition 870250096077, dated 10 / 21 / 2025, p. 203 / 378 199 / 297 O-R2x, -S0-R2, -SH, -S03H, -N3, -CHO, -COOH, -CONH2, -COSH, COR2X, -SO2NH2, alkenyl, alkynyl, alkoxyl, -NH-CH2-NH2, -CONH2, SO2NH2, -NH-, CS-NH2,K, orN; where: Each of R2x and R2Y is independently selected from the group consisting of H, -OH, -CH2-OH, -NH2, -CH2-NH2, -COOMe, COOH, -CONH2, -COCH3, alkyl, alkenyl, alkynyl, alicyclic, aryl, biaryl and heteroaryl, and each of R22 is independently selected from the group consisting of -NH2, -NR2qR2q', -O-R2q, -SO-R2q and -COR2q; wherein each of R2q and R2q' is independently alkyl or H; and It is a non-aromatic, mono- or bicyclic heterocycle containing N of 3-10 members; where, in Formula 2-1, each of X1, X2 and X3 is independently CRq or N, and each Rq is independently H, halogen or an optionally substituted alkyl; and where, in Formula 2-1, n is 0-30 and is 0-4. [000360] In certain modalities, the immunomodulator radical of the first therapy comprises a TLR agonist with the following formula: Petition 870250096077, dated 10 / 21 / 2025, pp. 204 / 378 200 / 297 where: RI is an amine group, R2 is a single -NH- bond, R3 is an H, an alkyl, a hydroxyl group or any other substituted group thereof, X is a CH2, NH, O or S, and the ligand is attached to RI, R2 or R3. [000361] In certain embodiments of the methods described herein, at least one compound (e.g., of the first therapy) is or comprises a structure of the following formula: It is either a pharmaceutically acceptable salt or carbohydrate thereof. [000362] The ligand of at least one compound (or a pharmaceutically acceptable salt or hydrate thereof) of the first therapy may be any ligand described herein. In certain embodiments, the ligand is a releasable ligand. In certain embodiments, the ligand is a non-releasable ligand. In certain embodiments, the ligand of at least one compound (or a pharmaceutically acceptable salt or hydrate thereof) of the first therapy comprises a PEG ligand or a PEG-derived ligand and is a non-releasable ligand. Petition 870250096077, dated 10 / 21 / 2025, page 205 / 378 201 / 297 [000363] The subject may be suffering from, or at risk of suffering from, cancer or a recurrence of cancer. In certain modalities, the administration step of the first therapy also includes administering or applying to the subject a therapeutically effective amount of at least one pharmaceutically acceptable compound or salt or hydrate thereof. [000364] In certain embodiments, administration of the second therapy (i.e., one or more checkpoint inhibitors) disrupts an immune checkpoint of a subject cell. One or more checkpoint inhibitors of the second therapy may be or comprise a small molecule or other agent that disrupts an immune checkpoint of a subject cell. Any of the checkpoint inhibitors described herein may be used.In certain modalities, one or more of the second-therapy checkpoint inhibitors are selected independently from the group consisting of pembrolizumab, nivolumab, ipilimumab, cemiplimab, atezolizumab, avelumab, durvalumab, pidilizumab, MEDI-0680 monoclonal antibody, REGN2810 monoclonal antibody or AMP-224 fusion protein targeting PD-1, ociperlimab, islelizumab, a combination of ociperlimab and islelizumab, BMS-936559 / MDX-l105, MPDL3280A / RG7446 / atezolizumab, MSB0010718C / avelumab or MEDI4736 / durvalumab, tiragolumab, zimberelimab, tremelimumab, relatlimab, IMP321 monoclonal antibody, nivolumab, etigilimab, domvanalimab, tiragolumab (RG6058) and vibostolimab.One or more immune checkpoint inhibitors of the second therapy may inhibit an immune checkpoint of a selected cell from a group consisting of PD-1, PD-L1, CTLA-4, VISTA, LAG3, TIM3, TIGIT, PD-L2, IDO, AGR1, B7-H3, B7-H4, 2B4, BTLA, A2aR and / or a member of the KIR family, such as KIRs and C-type lectin receptors, and STAT3. [000365] The pharmaceutically acceptable compound (or salt or hydrate of Petition 870250096077, dated 10 / 21 / 2025, pp. 206 / 378 202 / 297 itself) or a composition comprising it, or a combination thereof, and one or more immune checkpoint inhibitors may be administered to the individual using any suitable method known in the art. Examples of suitable routes of administration include, but are not limited to, oral, intravenous, intramuscular, subcutaneous, and transdermal. The compounds, compositions, and / or a combination thereof and one or more immune checkpoint inhibitors may be administered directly into the bloodstream, muscle, or internal organ. Suitable routes for parenteral administration include, but are not limited to, intravenous, intra-arterial, intraperitoneal, intrathecal, epidural, intracerebroventricular, intraurethral, ​​intrasternal, intracranial, intratumoral, intramuscular, and subcutaneous. Needle injectors, including microneedles, needleless injectors, and infusions may be used.The compounds, compositions and / or a combination thereof and one or more immune checkpoint inhibitors may be administered in single pharmaceutical forms and / or formulations containing conventional, non-toxic and pharmaceutically acceptable carriers or excipients (or vehicles or adjuvants), together in the same composition or in separate compositions. [000366] In the method, the pharmaceutically acceptable compound(s) or salt or hydrate(s) thereof (or pharmaceutical composition comprising the pharmaceutically acceptable compound(s) or salt(s) or hydrate(s) thereof and a pharmaceutically acceptable vehicle or excipient) and one or more immune checkpoint inhibitors may be administered simultaneously or sequentially, in any order, by the same route or by different routes. When administered simultaneously by the same route, the formulations may be the same or different. In several embodiments, the compound (or pharmaceutically acceptable salt or hydrate) Petition 870250096077, dated 10 / 21 / 2025, pp. 207 / 378 203 / 297 may be administered to the subject after the immune checkpoint inhibitor(s). The time between administration of the immune checkpoint inhibitor(s) and administration of the compound(s) may vary widely depending on factors including the type of immune checkpoint inhibitor(s) being used, the binding specificity of the compound (or pharmaceutically acceptable salt or hydrate thereof), the identity of the targeting fraction of the compound, the type of cancer, the location of the cancer in the subject, the means used to administer the immune checkpoint inhibitor(s) and the compound to the subject, as well as the subject's health, age, and weight. [000367] The compound(s) may be administered before or after the immune checkpoint inhibitor(s), such as approximately 3, 6, 9, 12, 15, 18, 21 or 24 hours, or approximately 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10 or more days. The administration rate of the compound and / or immune checkpoint inhibitor(s) may be adjusted, for example (depending on the dosing schedule, such as continuous, once daily, twice daily, three times daily, once weekly, twice weekly or three times weekly). "Continuous" means at least one hour, at least four hours, at least six hours, at least eight hours, at least 10 hours, at least 12 hours or at least 24 hours, or a daily or weekly administration schedule, such as once a day, twice a day, three times a day, on alternate days, once a week, twice a week, three times a week or any other suitable schedule.In this method, the immune checkpoint inhibitor(s) (or pharmaceutical composition comprising the immune checkpoint inhibitor(s) and a pharmaceutically acceptable carrier or excipient) and the compound can be administered intravenously. [000368] In certain approaches, the administration of the first and the Petition 870250096077, dated 10 / 21 / 2025, pp. 208 / 378 204 / 297 second therapies to the individual result in a greater than additive inhibition of cancer growth. [000369] The first therapy can be administered to an individual intravenously, orally, intramuscularly, intraperitoneally, topically, or by inhalation. The second therapy can be administered to an individual intravenously, orally, intramuscularly, intraperitoneally, topically, or by inhalation. [000370] The term “individual” means an animal, such as a mammal and, in particular, a human being. In veterinary applications, the individual may be a laboratory, farm, domestic, or wild animal. Examples of such animals include, among others, a rodent, a rabbit, a monkey, a chimpanzee, a dog, a cat, a cow, a horse, a pig, a sheep, a goat, a bear, a panda, a lion, a tiger, a leopard, an elephant, a zebra, a giraffe, a gorilla, a dolphin, or a whale. [000371] In some modalities, the methods are used to treat cancers, for example, regardless of whether the cancer expresses the folate receptor or not. In some modalities, folic acid and other folate receptor-binding ligands (or radicals thereof), such as folate, are used as targeting molecules, since, for example, they have an affinity for FRB. [000372] The methods described here may also include obtaining images of the cancer in the individual. Obtaining images of the cancer may include optical imaging, positron emission tomography (PET) or single-photon emission computed tomography (SPECT), for example. [000373] In the methods described herein, cancer may additionally be imaged before administration of the first or second therapy to the individual. Cancer may additionally, or alternatively, be imaged during or after administration of the first and / or Petition 870250096077, dated 10 / 21 / 2025, pp. 209 / 378 205 / 297 Second therapies to assess metastasis, for example, and the effectiveness of treatment. For example, imaging can be obtained by PET imaging, magnetic resonance imaging (MRI), or SPECT / computed tomography (CT). The imaging method can be any suitable imaging method known in the art. [000374] Cancer can be any type of cancer. “Cancer” has its simple and common meaning when read in light of the Descriptive Report and may include, but is not limited to, a group of diseases involving abnormal cell growth with the potential to invade or spread (i.e., metastasize) to other parts of the body. Examples include, but are not limited to, cancer of the brain, thyroid, lung, pancreas, kidney, stomach, gastrointestinal stroma, endometrium, cervix, ovary, colon, or prostate, leukemias, lymphomas, other blood-related cancers, and head and neck cancer. In certain modalities, the cancer treated is a tumor. In certain modalities, the cancer is malignant. In certain modalities, the cancer comprises a PD-L1+ tumor. [000375] In certain modalities, cancer comprises a hot tumor. In certain modalities, cancer comprises a cold tumor. In certain modalities, cancer comprises an immune desert tumor. A cold tumor is typically characterized by the absence of T cell infiltration (i.e., an immune desert) or a tumor in which T cells accumulate only at the edges of the tumor site. These types of tumors exhibit immunoignorance, low immunogenicity, and low resistance to immune checkpoint blockade therapy. On the other hand, hot tumors are typically characterized by a high degree of T cell infiltration or a tumor with pre-existing immunity, high immunogenicity, and generally exhibit a better response to immune checkpoint blockade therapy. [000376] In some modalities, the cancer is visualized before the Petition 870250096077, dated 10 / 21 / 2025, page 210 / 378 206 / 297 administration of the first and second therapies to the individual. Imaging can be done by PET, MRI or SPECT / CT, for example. [000377] The administration of the first and second therapies may be undertaken to treat cancer recurrence in an individual or resistance to checkpoint blocking therapy in an individual. [000378] In certain embodiments, the use of (i) a pharmaceutically acceptable compound, salt, hydrate or solvate of the compound, or (ii) a composition comprising a pharmaceutically acceptable compound, salt, hydrate or solvate thereof in the manufacture of a medicament for the treatment of cancer in an individual is provided. The compound may be any compound described herein. The composition may be any composition described herein. The medicament may be for use in combination with the administration of an immune checkpoint inhibitor therapy to the individual, such as, for example, one or more immune checkpoint inhibitors described herein. [000379] In addition, a method is provided for increasing the potency of one or more immune checkpoint inhibitors. The method may comprise administering to the subject one or more compounds of this document (or pharmaceutically acceptable salts or hydrates thereof) comprising a radical of an immune modulator or a pharmaceutically acceptable salt or hydrate thereof linked, via a ligand, to a folate ligand or functional fragment or analogue thereof; and contacting a target cell of the subject with the compound(s) to reprogram the subject's M2-type macrophages to M1-type macrophages. The compound(s) of this method may comprise any of the compounds described herein. The immune modulator or pharmaceutically acceptable salt or hydrate thereof may target a pattern recognition receptor. The compound(s) may be Petition 870250096077, dated 10 / 21 / 2025, page 211 / 378 207 / 297 formulated in a composition of this document further comprising one or more pharmaceutically acceptable carriers, adjuvants, diluents, excipients and / or vehicles, or combinations thereof. The immunomodulator or pharmaceutically acceptable salt or hydrate thereof may comprise a TLR 3, 7, 8, 9 or 7 / 8 agonist. In certain embodiments, administration of at least one compound acts on antitumor cells or an anti-inflammatory signaling cascade in the individual. Antitumor cells may be, for example, T cells, macrophages or both T cells and macrophages. [000380] In some embodiments, the method further comprises obtaining, or having obtained, a sample from the individual; measuring the expression level of one or more biomarkers in the sample, each of which is one or more biomarkers selected from the group consisting of CCL18, arginase 1 (Argl), matrix metallopeptidase 9 (MMP9), metalloproteinase 3 (TIMP 3), IL-1β, hydroxyproline, collagen, PDGF, TGFB, FRB, TNFα, IFN-γ, antimannose receptor (CD206), cluster of differentiation 86 (CD86), cluster of differentiation 163 (CD163), IL-6, chemokine 10 (CXCLl 0), immune interferon (IFNa); comparing the expression level of each of the one or more biomarkers in the sample with the expression level of that biomarker in a control;and administer or have administered to the subject a therapeutically effective amount of an unconjugated agonist or inhibitor if CCL18, Argl, MMP9, TIMP 3, IL1β, PDGF, TGFβ, FRβ, CD206, CD163, hydroxyproline, or collagen are upregulated relative to the control expression level, or TNFo, IFN-γ, IL-6, CXCL10, IFNa, or CD86 are upregulated or not expressed relative to the control expression level. In some modalities, the folate ligand or functional fragment or analog thereof is specific for FRβ and binds to an FRβ on the cell. [000381] Reprogramming of M2-type Macrophages to Macrophages of Petition 870250096077, dated 10 / 21 / 2025, p. 212 / 378 208 / 297 Type Ml [000382] In at least one embodiment, a method is provided for treating and / or preventing the recurrence of a cancer. The method comprises administering to the individual a therapeutically effective amount of one or more compounds comprising a targeting moiety (such as a folate receptor-binding ligand) linked to a drug (via a ligand or otherwise) to reprogram M2-type macrophages in the tissue or organ to an M1-type phenotype. For example, the drug may be a TLR agonist (e.g., with formula I, III, or IV) or any other molecule or compound that is effective in reprogramming an M2-phenotype macrophage to the folate-conjugated M1-phenotype. In at least one embodiment, the drug may be selected from a TLR 3 agonist, a TLR 7 agonist, a TLR 7 / 8 agonist, a TLR 8 agonist, and a TLR 9 agonist.In some modalities, the drug can reprogram M2-type macrophages to an M1 phenotype, thereby reducing the production of anti-inflammatory cytokines and growth factors. For example, in at least one modality, reprogramming M2-type macrophages to an M1 phenotype results in the activation of antitumor cells and / or an anti-inflammatory signaling cascade within the tumor microenvironment (TME). [000383] There are two main immunity strategies found in vertebrates: the innate immune system and the adaptive immune system. The innate, or non-specific, immune response is the first line of defense against non-self pathogens and consists of physical, chemical, and cellular defenses. The adaptive immune system, on the other hand, is activated against pathogens that escape or overcome the primary innate immune defenses. [000384] The inflammatory response plays a critical role in Petition 870250096077, dated 10 / 21 / 2025, page 213 / 378 209 / 297 Immunity. When tissues are damaged or a pathogen is detected, for example, an inflammatory response is initiated and the immune system is mobilized. Immune cells of the innate immune system (i.e., neutrophils and eosinophils) are the first to be recruited to the site of injury or tissue damage or to the location of the pathogen, via blood vessels and the lymphatic system, followed by macrophages. [000385] Cells of the innate immune system can express special pattern recognition receptors that detect and bind to specific protein sequences present in microbial pathogens or other non-self molecules. [000386] Examples of two classes of molecules that can bind to pattern recognition receptors include molecular patterns associated with microbial pathogens and damage-associated molecular patterns, associated with components of host cells, which are released during cell damage or death. Recognition of these protein sequences by pattern recognition receptors can initiate signal transduction pathways that trigger the expression of certain genes whose products control innate immune responses (e.g., in some cases, instructing the development of antigen-specific acquired immunity). Consequently, pattern recognition receptors mediate these signaling pathways and, in certain cases, can be used to positively or negatively control the innate—and even adaptive—immune response. [000387] Macrophages are a diverse group of leukocytes known for eliminating pathogens through phagocytosis and are broadly classified as having an M1 or M2 phenotype, depending on the specific differentiation they undergo in response to the local tissue environment. In some cases, macrophages are polarized towards the M1 phenotype by exposure to interferon gamma (IFN-γ), lipopolysaccharide. Petition 870250096077, dated 10 / 21 / 2025, page 214 / 378 210 / 297 (LPS) and / or granulocyte-macrophage colony-stimulating factor (GMCSF). In certain cases, the Ml phenotype is characterized by the production of high levels of pro-inflammatory cytokine(s) (such as interleukin 1B (IL-1B), tumor necrosis factor (TNF), interleukin 12 (IL-12), interleukin 18 (IL18), and / or interleukin 23 (IL-23)), the ability to mediate resistance to pathogens, strong microbicidal properties, high production of reactive nitrogen and oxygen intermediates, and / or promotion of type 1 helper T cell (Thl) responses. [000388] In other words, Ml polarization can activate antitumor cells, such as T cells (including, but not limited to, Thl cells) and macrophages (including, but not limited to, immunoprotective Ml tumor-associated macrophages (TAMs) and classically activated Ml myeloid-derived suppressor cells / MDSCs) in the TME). In some cases, Ml polarization is associated with the 'attack and kill' phase of the innate immune response, which can induce lysis in various types of cancer cells.Furthermore, the release of pro-inflammatory and tumoricidal cytokines (as well as the release of chemokines, leukotrienes, prostaglandins, and similar complement from M1 macrophages) can result in a general pro-inflammatory signaling cascade for the reactive function of T cells and affect the regulation of multiple genes and their transcription factors, which can result in the production of other cytokines, an increase in the number of surface receptors for other molecules that ultimately induce the recruitment of inflammatory cells. In addition to local effects, these mediators can also produce systemic effects, such as the production of acute inflammatory response proteins. In certain cases, M1 polarization acts to inhibit or prevent the initial establishment of infection and / or remove damaged / cancerous tissue; tumor growth and metastasis formation can be decreased by depletion of TAM M2, inhibition of M2 macrophage recruitment, and pro-inflammatory function. Petition 870250096077, dated 10 / 21 / 2025, pp. 215 / 378 211 / 297 tumoral, and by reprogramming M2 macrophages (e.g., TAMs and / or MDSCs) to the pro-inflammatory M1 phenotype. [000389] In certain cases, after the innate immune system completes this “attack and kill” phase, a macrophage can reprogram itself to become a healing system (i.e., M2 type) and, for example, release growth factors to promote healing. These growth factors may include (but are not limited to) certain cytokines such as interleukin 4 (IL-4), interleukin 10 (IL-10), platelet-derived growth factor (PDGF), transforming growth factor-β1 (TGFe), chemokine ligand 18 (CC motif) (CCL18), and / or interleukin 13 (IL-13). In certain cases, exposure to such cytokines / growth factors alternatively activates the M2 macrophage phenotype. [000390] In contrast to M1, M2 macrophages may be associated with wound healing and tissue repair. In some cases, M2 macrophages are characterized by their involvement in tissue remodeling, immune regulation / suppression, and / or tumor promotion. In specific cases, M2 macrophages produce polyamines to induce cell proliferation and / or proline to induce collagen production. While this healing response is beneficial in a healthy individual, the presence of M2 macrophages can have significantly detrimental effects through immunosuppression and / or the promotion of tumor growth and fibrosis in individuals with cancer. Chemokines and other factors may be released to promote the infiltration of immune cells into damaged tissue (e.g., an innate immune response), which, for example, includes monocytes and macrophages that assume M2-like phenotypes and, for example, release anti-inflammatory cytokines.Chronic secretion of these cytokines can then activate resident and tissue-infiltrated fibroblasts / fibrocytes, transforming them into myofibroblasts which, in turn, secrete collagen. Petition 870250096077, dated 10 / 21 / 2025, pp. 216 / 378 212 / 297 and other extracellular matrix proteins that can stiffen surrounding tissue. In some cases, these M2 macrophages exacerbate the disease, promoting fibrosis. In other cases, growth factors and other cytokines produced by the M2 phenotype drive cancerous tumor growth through similar pathways. [000391] In certain types of cancer, macrophages may be disproportionately biased toward the anti-inflammatory (M2-like) phenotype. In certain cases, immunomodulators can convert—for example, reprogram—activated myeloid cells (e.g., M2-like macrophages) into a pro-inflammatory M1 bias (e.g., where they produce few or no growth factors and / or related cytokines and, for example, slow or even eliminate the progression of the disease state (i.e., cancer)). In certain cases, combinations, compositions, and methods reverse the pro-inflammatory to anti-inflammatory shift observed during the development of certain types of cancer.In some modalities, the combinations, compositions, and methods decrease the quantity / expression of fibrotic biomarkers (e.g., those associated with anti-inflammatory activity (e.g., CCL18, hydroxyproline, and collagen)) in an individual or in a sample taken from a subject, which is indicative of the conversion of macrophages to the M1 phenotype and, therefore, of the activation of anti-tumor cells (e.g., T cells and / or macrophages) and the initiation of an anti-inflammatory signaling cascade. An “individual,” “subject,” or “patient” can be a mammal, preferably a human being, but can also be an animal. [000392] A “marker” or “biomarker” can be described as being differentially expressed when the level of expression in a subject who is in a state of active disease is significantly different. Petition 870250096077, dated 10 / 21 / 2025, pp. 217 / 378 213 / 297 of that of a subject or sample taken from a healthy subject or a subject who is not in a diseased state. A differentially expressed marker may be overexpressed or underexpressed compared to the expression level of a normal or control sample, or to the baseline of individuals (in the embodiment mentioned in the immediately preceding paragraph, the biomarker is decreased or underexpressed). The increase or decrease, or the quantification of markers in a biological sample, may be determined by any of several methods known in the art for measuring the presence and / or relative abundance of a gene product or transcript. The level of markers may be determined as an absolute value or relative to a baseline value, and the level of markers of individuals compared to a cutoff index. Alternatively, the relative abundance of the marker(s) can be determined relative to a control, which may be a clinically normal individual. Furthermore, the terms “gene overexpression” and “overexpression” (when used in connection with a gene) and their formatives have the meaning assigned to them by someone with common skill in the relevant techniques, which includes (without limitation) the overexpression or misexpression of a wild-type gene product that may cause mutant phenotypes and / or lead to abundant expression of the target protein. [000393] In some modalities, combinations, compositions, and methods increase antitumor biomarkers (e.g., TNFα and IFN-γ). In some modalities, combinations and compositions are provided that reverse M2-like phenotypic change (e.g., providing an effective treatment for cancers or related conditions). [000394] The administration of at least one compound (either salt or Petition 870250096077, dated 10 / 21 / 2025, pp. 218 / 378 214 / 297 pharmaceutically acceptable hydrate of the same) or composition of the first therapy may reprogram the subject's M2-type macrophages to M1-type macrophages and increase the potency of one or more checkpoint inhibitors of the second therapy relative to the baseline potency of one or more checkpoint inhibitors (e.g., baseline potency being when the checkpoint inhibitors are administered without combination with the first therapy). [000395] In some modalities, administration of the compounds or compositions (e.g., to a subject) can convert a macrophage into fibrotic tissue in the subject from an M2-like phenotype to an M1-like phenotype. The subject's M2-type macrophages may be MDSCs, TAMs, or both. MDSCs and TAMs. [000396] In some embodiments, there is a decrease in cytokines that stimulate collagen synthesis (i.e., CCL18, PDGF, and IL10) after administration of a compound or composition thereof, as well as a concomitant increase in cytokines that inhibit collagen production (e.g., IFN-γ). Notably, in at least one embodiment, after administration of the compounds or compositions, the cytokine profiles are consistent with reprogramming from the M2-like phenotype to the M1-like phenotype. A “profile” or “assay” is a set of one or more markers and their presence, absence, and / or relative level or abundance (relative to one or more controls). For example, a cytokine profile is a dataset of the presence, absence, relative level, or abundance of cytokines present in a sample.A genomic or nucleic acid profile is a dataset of the presence, absence, relative level, or abundance of expressed nucleic acids (e.g., transcripts, mRNA, or similar). A profile may alternatively be called an expression profile. [000397] In some modalities, the net consequence of Petition 870250096077, dated 10 / 21 / 2025, pp. 219 / 378 215 / 297 reprogramming is an increase in alveolar air sacs, a decrease in extracellular matrix deposition, and a reduction in hydroxyproline / collagen biosynthesis; an effective reversal of the disease (e.g., see Example 4). [000398] It should be understood that, although specific drugs and formulas are described herein, any compound (e.g., drug) useful for reprogramming activated myeloid cells into an M1-like antifibrotic phenotype may be used in the compounds, compositions, combinations, and methods described herein (e.g., any compound (e.g., drug) capable of binding to a pattern recognition receptor and inhibiting at least a portion of the downstream innate immune system response). In some embodiments, analogs and / or derivatives of a compound or a pharmaceutically acceptable salt or hydrate thereof may be used in the targeting compounds, compositions, and combinations. [000399] Furthermore, more than one compound may be administered and, in some cases, the compounds may comprise different drugs. For example, the different drugs may be selected from a TLR7 agonist and a TLR9 agonist. In yet another embodiment, one or more compounds may be administered in a combination together with one or more conjugated and / or unconjugated drugs. In some embodiments, any of the compounds and drugs may be used according to the methods described herein and, in some cases, depending on the desired application, may be combined with other drugs that deplete or inhibit myeloid-derived suppressor cells (e.g., in connection with cancer treatment), negatively regulate growth factor production (e.g., pirfenidone), directly modify fibroblasts by inhibiting target complex signaling of Petition 870250096077, dated 10 / 21 / 2025, pp. 220 / 378 216 / 297 rapamycin in mammals (mTORCl) and / or any other pro-inflammatory and / or anticancer drugs and therapies. “Negative regulation” and its formative terms (such as “negative regulation” or “negatively regulated,” for example) can be used interchangeably and refer to a decrease in the level of a marker, such as a gene, nucleic acid, metabolite, transcript, protein, or polypeptide. Similarly, “positive regulation” and its formative terms (“p-regulation” or “positively regulated,” for example) can also be used interchangeably and refer to an increase in the level of a marker, such as a gene, nucleic acid, metabolite, transcript, protein, or polypeptide. Furthermore, a pathway, such as a signal transduction or metabolic pathway, can be positively or negatively regulated. [000400] In certain embodiments, the method may comprise the delivery of a compound, a pharmaceutical composition comprising it, or a combination thereof (for example, a therapeutically effective amount of a compound or composition and one or more immune checkpoint inhibitors); and the exposure of the subject's M2-type macrophages to these; wherein the M2-type macrophages convert to an M1 phenotype that facilitates the activation of the subject's own immune response concomitantly with the administration of the compounds, compositions, and / or combinations thereof. [000401] Referring now to FIG. 2, a representative flowchart of a 1900 method for using one or more of the compounds (or pharmaceutically acceptable salts or hydrates thereof). In at least one case, the 1900 method comprises the steps of contacting a cell of a subject with (administering) at least one compound comprising an immunomodulator (or pharmaceutically acceptable salt or hydrate thereof), for example, and without limitation, a TLR7 agonist, linked, via a ligand, to a folate ligand or a functional fragment. Petition 870250096077, dated 10 / 21 / 2025, pp. 221 / 378 217 / 297 or an analogue thereof (step 1902). In at least one exemplary embodiment, the immune modulator or pharmaceutically acceptable salt thereof targets a pattern recognition receptor or a DAMP (i.e., via its targeting ligand). The cell may comprise, for example, a cell from a subject exhibiting, or at risk of exhibiting, cancer relapse or resistance, and at least one compound may comprise any of the compounds provided herein. [000402] In at least one embodiment, step 1902 of bringing a cell into contact with at least one compound (or pharmaceutically acceptable salts or hydrates thereof) further comprises administering or applying to the individual a therapeutically effective amount of at least one compound (or pharmaceutically acceptable salts or hydrates thereof). Additionally or alternatively, at least one compound (or pharmaceutically acceptable salts or hydrates thereof) may be formulated in a composition further containing one or more pharmaceutically acceptable carriers, adjuvants, diluents, excipients and / or vehicles, or combinations thereof. [000403] In at least one embodiment, the disease state comprises a cancer that is resistant to immune checkpoint therapy or that relapses after it. Because checkpoint inhibitors target adaptive immune cells, their combination with a drug that reprograms the innate immune system may be beneficial. Furthermore, since it has been established that MDSCs and TAMs can be reprogrammed to halt the growth cycle with FA-TLR7 and TLR7 / 8 agonists, systemic administration of these FA-TLR7 and / or FA-TLR7 / 8 agonists in combination with immune checkpoint inhibitors may target cancers exhibiting SHM, relapse, or resistance or ineffectiveness of treatment with the administration of the drug alone. Petition 870250096077, dated 10 / 21 / 2025, pp. 222 / 378 218 / 297 control point lock. [000404] In addition to step 1902, method 1900 may optionally comprise steps 1904 to 1910. In step 1904, a biological sample is obtained from the individual and, in step 1906, the expression level of one or more biomarkers in the sample is quantified. For example, the sample may be obtained from a quantity of peripheral blood collected from the individual. [000405] The quantification step 1906 can be performed using any appropriate method known in the art and may include, for example, qPCR, mass spectrometry, ELISA and / or any other modality capable of measuring / quantifying the expression of biomarkers. In at least one exemplary embodiment, one or more biomarkers are selected from the group consisting of CCL18, Argl, MMP9, TIMP 3, IL-1β, PDGF, TGFβ, FRβ, hydroxyproline, collagen, TNFα, IFN-γ, CD206, CD163, IL-6, CXCL10, IFNα and CD86. [000406] In step 1908, the expression level of each or more biomarkers in the sample is compared to the expression level of that biomarker in a control. The control may be a healthy individual or simply an individual who is not exhibiting the disease state in question. In at least one modality, a clinical difference between the expression level(s) of one or more biomarkers in the sample and the expression level of the related biomarker(s) in the control may be indicative that the subject suffers from the pathological state in question. For example, and without limitation, if the comparison step 1908 indicates that the expression of one or more of the biomarkers CCL18, Argl, CD163, MMP9, TIMP3, IL-1β, PDGF, TGFβ, FRβ, hydroxyproline, collagen and / or CD206 (i.e., the “anti-inflammatory biomarkers”) is increased compared to the control, this indicates that the subject has an anti-inflammatory immune response, which is linked to Petition 870250096077, dated 10 / 21 / 2025, pp. 223 / 378 219 / 297 macrophage phenotype similar to M2. Thus, in at least one embodiment, such a result is indicative of the need to administer one or more compounds of the present disclosure to reprogram such M2-type macrophages to the M1 phenotype. [000407] In contrast, if the comparison step 1908 indicates that the expression of the aforementioned biomarkers is downregulated compared to the control, or if the expression of one or more of TNFα, IFN-γ, and / or CD86 (the “pro-inflammatory biomarkers”) is upregulated compared to the control, this, in certain modalities, is indicative that the subject has a positive response to a previously administered compound (if applicable) and / or that the subject is exhibiting a pro-inflammatory immune response, which is linked to the M1 phenotype and the activation of one or more antitumor cells and / or an anti-inflammatory signaling cascade. [000408] Optionally, in step 1910, if the expression of one or more anti-inflammatory biomarkers in the sample is upregulated compared to the respective expression level(s) in the control, or if the expression of one or more pro-inflammatory biomarkers is downregulated in the sample compared to the respective expression level(s) in the control, an alternative therapy may be administered. In at least one embodiment, the alternative therapy may comprise the administration of a therapeutically effective amount of a derivative of at least one compound previously administered in step 1902, wherein the derivative comprises at least one previously administered compound modified with respect to the use of a different targeting fraction, a different ligand size, and / or a different immunomodulator, in an attempt to better optimize the efficacy of at least one compound for the subject. Additionally or Petition 870250096077, dated 10 / 21 / 2025, pp. 224 / 378 220 / 297 Alternatively, other treatments may be employed, including those conventionally known for the treatment of the cancerous disease in question (e.g., imaging, surgery, chemotherapy, radiation, etc.). Steps 1904-1910 may be included and / or repeated as necessary or desired to meet the established standard and / or confirm that the active ingredient(s) is / are effective in improving the manifestations of the cancerous disease state. [000409] As mentioned above, the methods can be used to treat and / or prevent cancer or its recurrence (whether folate receptor positive or folate receptor negative). For example, in certain cases, such a method comprises administering to the subject a therapeutically effective amount and / or a prophylactically effective amount of one or more compounds (or pharmaceutically acceptable salts or hydrates thereof) comprising a targeting fraction linked to a drug (via a ligand or otherwise) to reprogram M2-type macrophages in cancerous and / or tumor cells to an M1-type phenotype, such as, for example, a targeted TLR-7 agonist. When the cancer is folate receptor negative, such administration may additionally act to deplete or inhibit MDSCs present in such tissue / tumor.Additional medications may also be administered in connection with such methods, including, for example, a PI3k inhibitor, a signal transducer and activator of transcription 6 (STAT6) inhibitor, a mitogen-activated protein kinase (MAPK) inhibitor, an inducible nitric oxide synthase (iNOS) inhibitor, and an anti-inflammatory drug (e.g., methotrexate). In at least one embodiment, the medication may inactivate MDSCs. [000410] The compounds and compositions can be used alone or in combination with immunotherapy with a point inhibitor. Petition 870250096077, dated 10 / 21 / 2025, pp. 225 / 378 221 / 297 verification, so that cancer growth in the individual is inhibited. For example, in addition to step 1902, method 1900 may also include a step of administering checkpoint inhibitor immunotherapy (as described above). [000411] Such combination therapies are particularly beneficial in the treatment of cancers prone to recurrence or resistant to single therapy, resulting in the immune recognition of that cancer with the production of a systemic immune response and thus effectively attacking or even eliminating (e.g., causing remission) any remaining live cancer cells that possess the recognized antigen(s). As an important result, any remaining cancer can be eliminated or mitigated. Consequently, in certain approaches, the methods of this disclosure comprise treating an individual with a cancer that exhibits resistance to treatment with a checkpoint inhibitor. [000412] Such combination therapy methods can be performed using any suitable checkpoint inhibitor (as described above) and may include the use of more than one of these types of agents. The immune checkpoint inhibitor(s) used in combination with the compounds or compositions of the invention may be any immune checkpoint inhibitor. As is known in the art, examples of an immune checkpoint inhibitor include (without limitation) transmembrane programmed cell death protein 1 (PDCD1, PD-1: also known as CD279) and its ligand PD-L1 (also known as CD274). In normal, non-malignant physiology, PD-L1 on the surface of a cell ligase to PD1 on the surface of an immune cell, which inhibits the activity of the immune cell. Upregulation of PD-L1 on the surface of cancer cells is believed to facilitate immune system evasion. Petition 870250096077, dated 10 / 21 / 2025, pp. 226 / 378 222 / 297 host, at least in part, by inhibiting T cells that would otherwise target the tumor cell. In certain embodiments, one or more checkpoint inhibitors are each independently selected from the group consisting of pembrolizumab, nivolumab, ipilimumab, cemiplimab, atezolizumab, avelumab, durvalumab, pidilizumab, MEDI-0680 monoclonal antibody, REGN2810 monoclonal antibody or AMP-224 fusion protein targeting PD-1, ociperlimab, islelizumab, a combination of ociperlimab and islelizumab, BMS-936559 / MDX-1105, MPDL3280A / RG7446 / atezolizumab, MSBOO10718C / avelumab or MEDI4736 / durvalumab, tiragolumab, zimberelimab, tremelimumab, relatlimab, monoclonal antibody IMP321, nivolumab, etigilimab, domvanalimab, tiragolumab (RG6058), vibostolimab, avelumab and durvalumab. [000413] In certain approaches, administration of the compounds described herein (or pharmaceutically acceptable salts or hydrates thereof) and checkpoint inhibitor therapy results in greater than additive inhibition of cancer growth. [000414] When multiple therapeutic agents are co-administered, dosages may be adjusted appropriately, as recognized in the relevant technique. [000415] When a combination therapy method involves administering more than one treatment to an individual, it should be understood that the order, timing, number, concentration, and volume of administration are limited only by the medical requirements and limitations of the treatment (i.e., two treatments may be administered to the individual, for example, simultaneously or sequentially (in any order), or according to any other regimen). Petition 870250096077, dated 10 / 21 / 2025, pp. 227 / 378 223 / 297 [000416] In describing representative embodiments, the disclosure may have presented a method and / or process as a specific sequence of steps. To the extent that the method or process is not based on the specific order of steps set forth herein, the method or process should not be limited to the specific sequence of steps described. As one with common knowledge of the art would understand, other sequences of steps may be possible. Therefore, the specific order of steps disclosed herein should not be interpreted as limiting the Claims. Furthermore, Claims directed to a method and / or process should not be limited to performing its steps in the order described, and a person skilled in the art can easily understand that sequences can be tested and still remain within the spirit and scope of the present disclosure. [000417] Although various embodiments of compounds, compositions, and methods have been described in considerable detail herein, the embodiments are merely offered by way of non-limiting, exemplary figures. Many variations and modifications of the embodiments described herein will be apparent to one with common knowledge of the art in light of the disclosure. Therefore, it will be understood by those skilled in the art that various alterations and modifications may be made, and equivalents may be used to substitute elements thereof, without departing from the scope of the disclosure. Indeed, this disclosure is not intended to be exhaustive or overly limiting. The scope of the disclosure shall be defined by the appended Claims and their equivalents. [000418] Furthermore, although many of the examples given here use mouse models, it will be taken into consideration by anyone with common knowledge in the field that gene expression patterns in mouse models show extraordinarily significant correlations with those of human conditions, and many pathways are Petition 870250096077, dated 10 / 21 / 2025, pp. 228 / 378 224 / 297 commonly regulated by multiple conditions in humans and mice. Consequently, gene expression patterns and disease progression in mouse models closely mirror those in human conditions—particularly with regard to inflammatory diseases and cancers—and, as such, corroborate that the practical examples presented here correlate with human data, specified conditions, and applications. [000419] Therefore, this description and the attached Claims are intended to encompass all apparent modifications and changes to those with common knowledge in the field based on this disclosure. [000420] General [000421] For the purpose of promoting understanding of the principles of this disclosure, we will now refer to the embodiments illustrated in the drawings and use specific language to describe them. However, it should be understood that the description of these embodiments is not intended to limit the scope. Rather, this disclosure is intended to encompass alternatives, modifications, and equivalents that may be included within the spirit and scope of this application, as defined by the appended Claims. As noted above, although this technology may be illustrated and described in one or more preferred embodiments, the compositions, compounds, and methods described herein may comprise many different configurations, forms, materials, and accessories. [000422] All patents, patent application publications, journal articles, textbooks, and other publications mentioned in the Disclosure Report are indicative of the skill level of those in the art to which the disclosure relates. All such publications are incorporated herein by reference to the same extent as if each individual publication were specifically and individually indicated to be. Petition 870250096077, dated 10 / 21 / 2025, pp. 229 / 378 225 / 297 incorporated by reference. [000423] In the following description, several specific details are presented to provide a complete understanding of this disclosure. Particular examples may be implemented without some or all of these specific details, and it should be understood that this disclosure is not limited to specific biological systems, specific cancers, or specific organs or tissues, which may, of course, vary, but remain applicable in view of the data provided herein. [000424] Various techniques and mechanisms of the present disclosure will at times describe a connection or link between two components. Words such as attached, linked, coupled, connected, and similar terms with their inflectional morphemes are used interchangeably unless the difference is observed or clarified by the context. These words and expressions do not necessarily mean direct connections, but include connections through mediating components. It should be noted that a connection between two components does not necessarily mean a direct and unimpeded connection, since a variety of other components may reside between the two relevant components. Consequently, a connection does not necessarily mean a direct and unimpeded connection unless otherwise indicated. [000425] Furthermore, whenever possible and convenient, similar reference numbers are used in the FIGS. and in the description to refer to the same parts or steps or similar parts. The drawings are in a simplified form and not to precise scale. It is understood that the disclosure is presented in this manner merely for explanatory purposes and the principles and embodiments described herein may be applied to compounds and / or compositional components having configurations different from those specifically described herein. In fact, it is expressly contemplated that the compositional components and the Petition 870250096077, dated 10 / 21 / 2025, pp. 230 / 378 226 / 297 compounds of this disclosure may be adapted to promote the desired application. [000426] In certain embodiments, the compounds, compositions, and methods described herein are useful for the prevention and / or treatment of cancer. In certain embodiments, the compounds and / or compositions provided are also useful for the treatment of cancer. In some embodiments, the compounds, compositions, and methods provided herein leverage strategies to (e.g., selectively) target the innate immune system and reprogram the polarization of an M2 to M1 macrophage, for example, potentiating its checkpoint blocking properties. In some embodiments, the compounds comprise Toll-like receptor agonists TLR7 and / or 8. In certain embodiments, the compounds provided herein are provided or used alone, in conjunction with a targeting agent, and / or in a combination therapy with other interventions. [000427] Certain Definitions [000428] The following terms and phrases will have the meanings set forth below. Unless otherwise defined, all technical and scientific terms used herein have the same meaning commonly understood by a person skilled in the art. [000429] The term “about” or “approximately” means within an acceptable range for the specific value, as determined by a person skilled in the art, which will depend in part on how the value is measured or determined, for example, on the limitations of the measuring system. For example, “about” may mean a range up to 20%, preferably up to 10%, more preferably up to 5%, and even more preferably up to 1% of a given value. By way of further example, “about” or “approximately” may mean within 90%, within 95%, 99%, 99.5%, 99.9%, 99.99%, or by Petition 870250096077, dated 10 / 21 / 2025, pp. 231 / 378 227 / 297 less approximately 99.999% or more of a stated value or a stated limit of a range. Alternatively, particularly with regard to biological systems or processes, the term may mean within an order of magnitude, preferably within 5 times, and more preferably within 2 times, of a value. Unless otherwise indicated, the term “approximately” means within an acceptable error range for the specific value, such as ± 1-20%, preferably ± 1-10%, and more preferably ± 1-5%. [000430] When a range of values ​​is provided, it is understood that each intermediate value, between the upper and lower limits of that range and any other declared or intended value within that range, is covered. The upper and lower limits of those smaller ranges may be included independently within the smaller range intervals, and are also covered, subject to any limit specifically excluded within the declared range. When the declared range includes one or both limits, the ranges that exclude one or both limits are also included. [000431] A phrase that refers to “at least one of” a list of items refers to any combination of those items, including individual members. For example, “at least one of a, b, or c” is intended to encompass: a, b, c, ab, ac, bc, and abc. [000432] The terms “a,” “an,” or “the” are used to include one or more than one, unless the context clearly indicates otherwise. The term “or” is used to refer to a non-exclusive “or,” unless otherwise indicated. Furthermore, it should be understood that the phraseology or terminology employed herein, and not otherwise defined, is for descriptive purposes only and not limiting purposes. [000433] The term “or” is used to refer to a non-exclusive “or,” unless otherwise indicated. Furthermore, it should be understood that the Petition 870250096077, dated 10 / 21 / 2025, pp. 232 / 378 228 / 297 Phraseology or terminology employed herein, and not otherwise defined, is for descriptive purposes only and not for limitation purposes. [000434] Terms and expressions employed are used as descriptive and not limiting terms. Where certain terms are defined and described or otherwise discussed elsewhere in the “Detailed Description,” all such definitions, descriptions, and discussions shall be attributed to such terms. Nor is there any intention in the use of such terms and expressions to exclude any equivalents of the features shown and described or parts thereof. Furthermore, although subheadings may be used in the “Detailed Description,” such use is only for ease of reference and is not intended to limit any disclosure made in a section to that section only; rather, any disclosure made under a subheading is intended to constitute a disclosure under all other subheadings. [000435] It is recognized that various modifications are possible within the scope of the claimed invention. Thus, although the present invention has been specifically disclosed in the context of preferred embodiments and optional features, those skilled in the art may resort to modifications and variations of the concepts disclosed herein. Such modifications and variations are considered within the scope of the invention as claimed herein. EXAMPLES [000436] The following examples serve to illustrate the present disclosure. The examples are not intended to limit the scope of the claimed invention in any way. CHEMISTRY EXAMPLES Petition 870250096077, dated 10 / 21 / 2025, pp. 233 / 378 229 / 297 Example A: Synthesis of Compound ΙΑ [000437] Compound IA was synthesized according to Scheme 1 below and as reported by Nikunj M. Shukla, Cole A. Mutz, Subbalakshmi S. Malladi, Hemamli J. Warshakoon, Rajalakshmi Balakrishna, and Sunil A. David, “Regioisomerism-dependent TLR7 agonism and antagonism in an imidazoquinoline; Structure-Activity Relationships in Human Toll-Tike Receptor 7 Active Imidazoquinoline Analogs”, J Med Chem. February 9, 2012; 55(3): 1106-1116. Scheme 1 V. C^jCOCL EtjN 21. CaO, 11. 3· chloroperoxybenzoic acid 2 / . benzoyl isocyanate 3 / · NaOCH,_______________ Step 1: Synthesis of l-amino-2-methylpropan-2-ol (compound) [000438] 2,2-dimethyloxirane (0.1 g, 1.388 mmol) was added dropwise to 20 mL of ice-cooled ammonium hydroxide solution. The reaction mixture was stirred for 12 hours at room temperature. The Petition 870250096077, dated 10 / 21 / 2025, pp. 234 / 378 230 / 297 solvent was removed under running water and the residue was dissolved in methanol. Di-tert-butyl dicarbonate (0.75 g, 3.47 mmol) was added to the reaction mixture and stirred for 4 hours. The mixture was purified by column chromatography (24% ethyl acetate (EtOAc) / hexane) to obtain tert-butyl 2-hydroxy-2-methylpropylcarbamate. The pure tert-butyl 2-hydroxy-2-methylpropylcarbamate was dissolved in 5 mL of trifluoroacetic acid and stirred for 35 minutes. The solvent was removed under reduced pressure to give l-amino-2-methylpropan-2-ol as the trifluoroacetate salt l'. 500 MHz 1H NMR (500 MHz, CDC13, 8 in ppm): 8 8.62 (s, 2H), 3.02 (d, 2H), 2.06-2.04 (m, 2H), 1.37-1.34 (s, 6H). [000439] Step 2: Synthesis of 2-methyl-1-(3-nitroquinolin-4ylamino)propan-2-ol (compound 2) [000440] The trifluoroacetate salt of 1-amino-2-methylpropan-2-ol (compound) (450 mg, 2.4 mmol) was added to a solution of 4-chloro-3-nitroquinoline (compound 1) (250 mg, 1.2 mmol) and E13N (0.5 ml, 3 mmol) in a 4:1 mixture of toluene and 2-propanol. The mixture was heated to 70 °C for half an hour until a solid began to precipitate. The reaction mixture was then cooled, filtered, and washed with toluene / 2-propanol (7:3), ether, and cold water. The residue was dried at 80 °C to obtain 2-methyl-1-(3-nitroquinolin-4-ylamino)propan-2-ol (compound 2). Liquid chromatography-mass spectrometry (LCMS) analysis: [M+Ht m / z = 261. [000441] Step 3: Synthesis of 1-(3-aminoquinolin-4-ylamino)-2methylpropan-2-ol (compound 3) [000442] 2-methyl-1-(3-nitroquinolin-4-ylamino)propan-2-ol (compound 2) (450 mg, 1.72 mmol) was dissolved in methanol and hydrogenated over Pd / C as a catalyst with a hydrogen balloon for 4 hours. The solution was then filtered using celite, followed by evaporation of the solvent under reduced pressure to give 1-(3-aminoquinolin-4-ylamino)-2-ethylpropan-2-ol Petition 870250096077, dated 10 / 21 / 2025, pp. 235 / 378 231 / 297 (compound 3). LCMS: [M+Ht m / z = 231. 500 MHz H NMR (CDC13, 8 in ppm): 8 8.12 (s, 1H), 7.61-7.58 (m, 1H), 7.48-7.40 (m, 2H), 4.90 (s, 2H), 3.47 (2H), 1.35-1.21 (s, 6H). [000443] Step 4: Synthesis of 1-(4-amino-2-butyl-1H-imidazo[4,5c]quinoline]-1-yl)-2-methylpropan-2-ol (compound 5, TLR7A) [000444] To a solution of compound 3 (100 mg, 0.43 mmol) in anhydrous THF, triethylamine (66 mg, 0.65 mmol) and valeryl chloride (62 mg, 0.52 mmol) were added. The reaction mixture was then stirred for 6 to 8 hours, followed by solvent removal under vacuum. The residue was dissolved in EtOAc, washed with water and brine, and then dried over Na2SO4 to obtain the intermediate amide compound. This was dissolved in methanol (MeOH), followed by the addition of calcium oxide, and heated in a microwave at 110 °C for 1 hour. The solvent was then removed and the residue was purified by column chromatography (9% MeOH / dichloromethane) to obtain compound 4 (58 mg). To a solution of compound 4 in a solvent mixture of MeOH:dichloromethane:chloroform (0.1:1:1), 3-chloroperoxybenzoic acid (84 mg, 0.49 mmol) was added and the solution was refluxed at 45-50 °C for 40 min. The solvent was then removed and the residue was purified by column chromatography (20% MeOH / dichloromethane) to obtain the oxide derivative (55 mg). This was then dissolved in anhydrous dichloromethane, followed by the addition of benzoyl isocyanate (39 mg, 0.26 mmol) and heated at 45 °C for 15 min. The solvent was then removed under vacuum and the residue was dissolved in anhydrous MeOH, followed by the addition of excess sodium methoxide. The reaction mixture was then heated at 80 °C for one hour. The solvent was removed under vacuum, and the residue was purified using column chromatography (11% MeOH / dichloromethane) to obtain compound 5. LCMS: [M+Ht m / z = 312. HNMR 500 MHz (CDC13, 0 in ppm): 0 8.16-8.15 (d, 1H), 7.77-7.46 (d, Petition 870250096077, dated 10 / 21 / 2025, pp. 236 / 378 232 / 297 1H), 7.46-7.43 (m, 1H), 7.33-7.26 (m, 1H), 3.00-2.97 (m, 2H), 1.84-1.78 (m, 2H), 1.47-1.41 (m, 2H), 1.36 (s, 6H), 0.98-0.95 (m, 3H). Example B: Synthesis of Compound IB [000445] Compound IA can then be used to synthesize compound IB according to scheme 2 below. Scheme 2 [000446] Compound IA, folate, and ligand are commercially available or can be prepared according to the knm,vn methods for the specialist in the field. [000447] The heterobifunctional ligand 7 (88 mg, 0.213 mmol) was added to a solution of compound 5 (33 mg, 0.106 mmol) and dimethylaminopyridine (39 mg, 0.319 mmol) in 4 mL of methylene chloride at room temperature under a nitrogen atmosphere, and the mixture was Petition 870250096077, dated 10 / 21 / 2025, pp. 237 / 378 The mixture was stirred at reflux temperature for 7 hours, at which point thin-layer chromatography (TLC) analysis indicated >80% conversion. The mixture was concentrated and purified by column chromatography using 10% acetonitrile in methylene chloride as eluent. The pure product, compound 9, was obtained as a light yellow solid. A solution of compound 8 (1 eq.) in dimethyl sulfoxide (DMSO) was added in 3 parts, at 20-minute intervals, to a drug-ligand solution incorporating compound 9 (1.0 eq. - 1.5 eq.) in DMSO with dimethylaminopyridine (1 eq.). After 1 to 2 hours of stirring at room temperature under an argon atmosphere, LCMS analysis of the mixture indicated the formation of the desired folate-drug compound (compound 10) as the main product. The mixture was purified by preparative high-performance liquid chromatography (HPLC). LCMS: [M+Ht m / z = 959.1H RMN (500 MHz, DMSO-d6) o 8.58 (s, lH), 8.49 (d, J = 8.8 Hz, lH), 7.90 (d, J = 8.3 Hz, lH), 7.83 - 7.74 (m, lH), 7.54 (d, J = 8.0 Hz, 2H), 7.48 (t, J = 7,G Hz, lH), 7.41 (s, lH), 7.06 (s, lH), 6.81 (d, J= 6.2 Hz, lH), 6.61 (d, J= 8.3 Hz, 2H), 6.27 (s, lH), 4.43 (d, J= 5.9 Hz, 2H), 4.28 (t, J= 6.6 Hz, 2H), 4.00 (d, J= 25.7 Hz, 3H), 3.03 (t, J= 7.5 Hz, 2H), 2.97 (dd, J= 13.0, 6.5 Hz, lH), 2.09 (s, 2H), 1.81 (s, 7H), 1.40 (q, J= 7.4 Hz, 2H), 1.22 (s, 2H), 1.13 (s, 2H), 0.91 (t, J=7.4 Hz, 3H). Example C: Síntese do Composto 2A [000448] The 2A package will be sent to you by Esquema 3 and Esquema 4. Esquema 3 Petition 870250096077, on 10 / 21 / 2025, page. 238 / 378 234 / 297 (i) 20% piperidina, DMF (ii) Fmoc-Giu(OtBu}-COOH, pyBop, DIPEA. DMF (ill) 20% piperidina, DMF (iy) ácido pteroico, pyBop, DIPEA. DMF (i) 50% NHaDMF (ii) TFA:TIPS:H;O:TCEP Esquema 4 Petition 870250096077, dated 10 / 21 / 2025, pp. 239 / 378 235 / 297 [000449] Wang resin (11) loaded with cysteine ​​was initially deprotected using 20% ​​piperidine in dimethylformamide (DMF). The free amine was treated with Fmoc-Glu(OtBu)-COOH in the presence of benzotriazole-1-1-oxytripyrrolidinophosphonium hexafluorophosphate (PyBop), N,N-diisopropylethylamine (DTPEA) and DMF. The coupled product was deprotected using 20% ​​piperidine in DMF and treated with pteroic acid in the presence of PyBop, DTPEA and DMF, yielding compound 12. Petition 870250096077, dated 10 / 21 / 2025, pp. 240 / 378 236 / 297 The trifluoroacetyl group was deprotected with a 50% ammonia-DMF solution. Finally, the resin was cleaved using a trifluoroacetic acid:triisopropylsilane:water:tris(2-carboxyethyl)phosphine cocktail solution and purified by HPLC to obtain folate-cysteine ​​(13) as a yellow-colored solid. [000450] Compound 14 was initially treated with a heterobifunctional ligand reagent (15) to obtain the folate-cystine disulfide intermediate (16). This was then reacted with folate-cysteine ​​(13) in DMSO and purified by HPLC to produce compound 17 (i.e., Compound 2A). Characterization of all compounds was performed by LCMS using ammonium bicarbonate and acetonitrile as buffer systems. The LCMS-observed mass for compound 2A was [M+H]+ = 1082.2. Example D: Synthesis of the TLR7 agonist TLR7-1A [000451] Solvents, reagents, and starting materials were purchased from commercial suppliers and used as received, unless otherwise indicated. All reactions were carried out at room temperature, unless otherwise indicated. Starting materials were purchased from commercial sources or synthesized according to the methods described herein or using procedures from the literature. [000452] The synthesis of the TLR7 agonist TLR7-1A is described in Scheme 5: Scheme 5 Petition 870250096077, dated 10 / 21 / 2025, pp. 241 / 378 237 / 297 Pd / C, H2 Balloon Methanol, 4h Petition 870250096077, dated 10 / 21 / 2025, pp. 242 / 378 238 / 297 (i) Trichloroacetyl isocyanate, 45bC, min (ίΐ) NaCMe;MeOH, 75 °C: Example E: Synthesis of the TLR7 agonist TLR7-1B [000453] The synthesis of the TLR7 agonist TLR7-1B is described in Scheme 6: Scheme 6: Petition 870250096077, dated 10 / 21 / 2025, pp. 243 / 378 239 / 297 Example F: Synthesis of the TLR7 agonist TLR7-1C [000454] The synthesis of the TLR7 agonist TRL7-1C is described in Scheme 7: Scheme 7: Petition 870250096077, dated 10 / 21 / 2025, pp. 244 / 378 240 / 297 NHBK Example G: Synthesis of the releasable TRL7-folate compound [000455] The synthesis of the releasable TRL7-folate compound is described in Scheme 8: Scheme 8: Petition 870250096077, dated 10 / 21 / 2025, pp. 245 / 378 241 / 297 (i) 20% piperidine, DMF Wang resin pts FtPOÍ? (jj 20% piperidine) (fii WlW ptffcp. DiPE.A, (iii) 20% piperidine, DMF (iv) pteroic acid, pyBop, DIPEA, DMF Petition 870250096077, dated 10 / 21 / 2025, pp. 246 / 378 242 / 297 Example H: Synthesis of the Unreleased TRL7-Folate Compound [000456] The synthesis of the unreleased TRL7-Folate compound is described in FIG. 9: Scheme 9 Petition 870250096077, dated 10 / 21 / 2025, pp. 247 / 378 243 / 297 Ce^CCl,. DMF. 5» Example 1: Synthesis of the Unreleased TRL7-Folate Compound [000457] The synthesis of the unreleased TRL7-Folate compound (Compound 1000) is described in Scheme 10: Scheme 10 Petition 870250096077, dated 10 / 21 / 2025, pp. 248 / 378 244 / 297 B'-PCG.-NWlX NrH. THF, that's it. ¢) TFA CHaCt HD foéib -Hus, oipea DUSO Example J: Synthesis of the Unreleased TLR7-Folate Compound [000458] The synthesis of the unreleased TLR7-Folate compound is described in Schemes 11 and 12: Scheme 11 Petition 870250096077, dated 10 / 21 / 2025, pp. 249 / 378 245 / 297 Scheme 12 Petition 870250096077, dated 10 / 21 / 2025, pp. 250 / 378 246 / 297 „ >^-ΙНΗ-0ΟΪ Br CsjCCj, DMF, 719¾. 5h (III) NaCUe. UaOH (iv) TRA, CH,CÍ, (I) McPB*. CHjCIj (ii) CljCCOMCO, CHjCtj I PyRcfi, mPEÀ, DMF (1) tria (í-aminaachjtJ amine, DMF, 1h W FOlaw-NHS. DIPEA CMSO [000459] In conjunction with the current state of the relevant art, especially in view of the Schemes presented above, this disclosure provides sufficient detail for a professional with average knowledge of the art to use the concepts presented here to synthesize all other compounds in this disclosure. EXAMPLES Methods and Materials [000460] Human THP-1 monocytic cells were obtained from the American Type Culture Collection and cultured in RPMI 1640 medium. Petition 870250096077, dated 10 / 21 / 2025, pp. 251 / 378 247 / 297 folate-deficient (Invitrogen, Carlsbad, CA) containing 10% heat-inactivated fetal bovine serum and 1% penicillin / streptomycin (Invitrogen, Carlsbad, CA). THP-1 cells were initially selected as a model system because this human monocytic cell line is known to acquire an M2-like phenotype and produce significant amounts of anti-inflammatory cytokines after stimulation with IL-4, IL-6, and IL-13. [000461] All reagents were purchased from commercial sources and used without further purification. All other cell culture reagents, syringes, and disposable items were purchased from VWR (Chicago, IL). [000462] Anti-CTLA-4 (Cat#BE0131, clone: ​​9Hl0), anti-PD-I (Cat#BE0273, clone: ​​29F.1Al2) and anti-PDLl (Cat# BE0l0l, clone: ​​10F.9G2) antibodies were acquired from Bio X Cell (Lebanon, NH). [000463] The antibodies for flow cytometry, the Zombie Violet™ Fixable Viability kit, the fixation / permeabilization buffer, and the red blood cell lysis buffer were obtained from BioLegend (San Diego, CA). [000464] The mouse tumor dissociation kit (Cat# 130096-730) was purchased from Miltenyi Biotech. All flow cytometry sample analyses were performed on the Attune NXT analyzer. [000465] IFN-γ, IL-4, interleukin-6 (IL-6), and interleukin-13 (IL-13) were obtained from BioLegend. Phorbol 12-myristate 13-acetate (PMA), lipopolysaccharide (LPS), and all other reagents and solvents were purchased from Sigma. Example 1 Differentiation and polarization of THP-1 cells into M2-type macrophages in vitro Petition 870250096077, dated 10 / 21 / 2025, pp. 252 / 378 248 / 297 [000466] THP-1 cells were seeded in 96-well plates at a density of 60,000 cells / well. Cells were differentiated into non-polarized macrophages by 48 hours of incubation with 200 nM PMA, followed by 24 hours of incubation in fresh RPMI medium. The resulting macrophages were polarized to an M2-like phenotype by incubation with 20 ng / mL IL-4, 20 ng / mL IL-13, and 5 ng / mL IL-6 for 3 days, and then reprogrammed with different concentrations of Compound IA and Compound IA for 48 hours and collected for genetic analysis by quantitative polymerase chain reaction (qPCR). Cultures were maintained at 37 °C in a humidified incubator with 5% CO2. [000467] To assess whether a potent TLR7 agonist (e.g., Compound 1A; e.g., formula III) could reprogram anti-inflammatory macrophages into a pro-inflammatory phenotype, IL-4, IL-6, and IL-13-stimulated THP-1 cells were incubated with different concentrations of untargeted Compound 1A, and mRNA levels of several anti-inflammatory markers were examined—namely, CCL18, CD206, IL-1B, and PDGFα and B.[000468] As shown in FIG. 3A-3C, incubation with Compound 1A for 48 hours induced a decrease in the expression of CCL18, CD206, and IL-1B, suggesting that the TLR7 agonist may indeed promote a shift in these anti-inflammatoryally polarized THP-1 cells toward a less fibrotic / more inflammatory phenotype. Furthermore, when the expression of TNFα, a marker of a pro-inflammatory phenotype, was examined, an increase in its expression was observed (FIG.3D), confirming that the change of THP-1 from anti-inflammatory to pro-inflammatory properties had occurred. Example 2 Petition 870250096077, dated 10 / 21 / 2025, pp. 253 / 378 249 / 297 Assessment of macrophage reprogramming [000469] To confirm that the folate-conjugated TLR7 agonist can cause the same THP-1 reprogramming observed in Example 1, Compound 1B was prepared in which a releasable ligand connecting folate to Compound 1A was constructed with an autoimmune disulfide linkage to allow the release of Compound 1A after internalization of Compound 1B in the reducing environment of intracellular endosomes. [000470] Different concentrations of Compound 1A or Compound 1B were incubated with the above-polarized THP-1 macrophages for the times indicated, after which the culture medium was harvested for analysis of secreted cytokines and collection of cells for qPCR analysis. [000471] Total RNA was isolated from 1 x 10⁵ - 2 x 10⁵ macrophages using a Quick-RNA™ MicroPrep kit (Zymo Research, Irvine, CA) according to the manufacturer's recommended protocol. RNA samples were then reverse transcribed into cDNA using high-throughput cDNA reverse transcription kits (Applied Biosystems, Foster City, CA; #4368814). qPCR analyses were performed using the iTaq™ Universal SYBR Green SuperMix (Bio-Rad Laboratories GmbH, Hercules, CA; #1725121), the iCycler thermocycler, and the iCycler iQ 3.0 software (BioRad Laboratories GmbH, Hercules, CA) to track the expression of markers characteristic of macrophage polarization states. IL6, CXCL10, IFN-α, IFN-γ, and CD86 were used as markers for an M1 phenotype, while CCL18, CD206, CD163, and Arg1 were employed as markers for the M2 phenotype. IL-1B, PDGFB, MMP9, and TIMP3 were measured as indicators of an anti-inflammatory phenotype.IRAK-4 was used as an indicator of TLR7 stimulation. To control the specificity of the amplification products, an analysis of... was performed. Petition 870250096077, dated 10 / 21 / 2025, pp. 254 / 378 250 / 297 melting curve. No amplification of non-specific products was observed in any of the reactions. Each sample was analyzed independently in triplicate for each marker. [000472] By repeating the studies described above (see gray bars, FIGS. 3A-3F), the same qualitative changes were observed, only the magnitude of the impact of Compound lB was slightly reduced. This reduction in potency was expected because the non-targeted TLR7 agonist enters cultured cells immediately, while its folate-targeted counterpart is designed to enter cells only after binding to the folate receptor and receptor-mediated endocytosis. [000473] Data shown in FIGS. FIGS. 3A-3C support that administration of the non-targeted TLR7 agonist or the agonist of TLR7-targeted antibodies successfully reprogrammed M2-type macrophages to M1-type macrophages (i.e., they upregulated anti-inflammatory M2-type macrophages), and the data shown in FIGS. 3D-3F support that administration of the tested compounds increased the expression of M1-type macrophages. [000474] FIGS. 4A-4E and 5A-5D show representative graphical data of various marker levels measured in THP-1-induced M2 macrophage cells that were subsequently incubated with different concentrations of Compound 1B or Compound 1A for 2 hours, washed with PBS for the data shown in FIGS. 5A-5D, and then incubated again for 46 hours (for the data shown in FIGS. 4A-4E, cells were collected immediately after the initial 2 hours of incubation). In both datasets, cells were collected for genetic analysis by qPCR. FIGS. Figures 4A-4C show the mRNA levels of CCLI 8 (FIG. 4A and FIG. 5A), mRNA levels of CD206 (FIG. 4B and FIG. 5B), mRNA levels of IL-Iβ (FIG. 4C and FIG. 5C), and mRNA levels. Petition 870250096077, dated 10 / 21 / 2025, pp. 255 / 378 251 / 297 of PDGFe (FIG. 4E). The data corroborate that the M2-type anti-inflammatory phenotype was downregulated after administration of the tested compounds. In particular, Compound 1B downregulated macrophage anti-inflammatory / M2-type markers more than Compound 1A. Furthermore, FIG. 4D shows CD86 mRNA levels and FIG. 5D shows TNFu levels, whose data corroborate the hypothesis that the M1-like phenotype was upregulated after administration of the tested compounds. FIGS. 4A-4E and 5A-5D corroborate the hypothesis that the M2-type anti-inflammatory phenotype was downregulated after administration of the free and targeted TLR7 agonist. Although collected, data are not presented for PDGFu, as no significant difference was observed after treatment. [000475] Because low molecular weight water-soluble drugs, such as Compound IA and Compound IB, are frequently excreted from the body within 2 hours of injection, a more physiologically relevant in vitro model of in vivo drug exposure is to limit the incubation of a cell with the drug to only two hours and then examine the drug efficacy after a further 46 hours of incubation in the absence of the drug. As shown in FIGS. 4A-4E, when THP-1 cells were incubated with the TLR7 agonists for 2 hours before replacing the drug-containing compound with a drug-free compound, Compound IA was observed to exhibit superior potency compared to Compound IA, especially in the case of TNFu induction, where the folate-targeted compound was dramatically improved.This is likely due to the fact that the folate-targeted TLR7 agonist was taken up by folate receptor-positive cells, while Compound IA was not retained by the same cells. [000476] These data corroborate that Compound 1B should be more effective in reprogramming anti-inflammatory macrophages in vivo, with the Petition 870250096077, dated 10 / 21 / 2025, pp. 256 / 378 252 / 297 An additional advantage is that the folate-conjugated drug (e.g., Compound 1B) should also cause less systemic toxicity, as it is concentrated in macrophages expressing FR0 and is unable to penetrate folate receptor-negative cells that predominate throughout the body (e.g., Compound 1B was designed to be impenetrable to folate receptor-negative cells). [000477] FIGS. 6A-6D show representative graphical data of various marker levels measured in M2-induced THP-1 macrophages treated with different drug concentrations for 48 hours (FIGS. 6A and 6B) or for 2 hours, then displaced with fresh medium and cultured for the remaining 46 hours (FIGS. 6C and 6D). In both cases, cell supernatants were collected and CCL18 and IL-10 proteins were secreted by ELISA. The data corroborate that administration of the TLR7 compound or the folate-targeted TLR7 compound negatively regulates CCL18 and IL-10 secretion at low concentration ranges (0.1-10 nM). [000478] Furthermore, to ensure that the above mRNA analyses accurately reflected the levels of anti-inflammatory cytokines produced by IL-4, IL-6, and IL-13-stimulated THP-1 cells, the concentrations of CCL18 and IL-10 polypeptides in the THP-1 supernatants were quantified by ELISA assay. As shown in FIGS. 6A and 6B, both Compound 1A and Compound 1B induced reductions in CCL18 and IL-10 when continuously incubated with agonist for 48 hours; however, Compound 1B was again found to be superior when drug exposure was limited to only 2 hours (see FIGS. 6C and 6D). Example 3 Characterization of FR / 3 expression by flow cytometry Petition 870250096077, dated 10 / 21 / 2025, pp. 257 / 378 253 / 297 [000479] To measure FR0 expression in THP-1-derived macrophages, a fluorescence-activated cell sorter (FACS) analysis was performed. Cells were detached using Accutase Cell Detachment Solution (BioLegend, San Diego, CA; #423201) and carefully lifted with a cell scraper. Cells were washed with PBS and nonspecific binding was blocked by incubation with Fe2 receptor blocking solution (BioLegend, San Diego, CA; #422301) at room temperature for 10 min. Biotinylated human anti-FR0 monoclonal antibody (m909) was then added and cells were incubated for a further 30 min on ice before washing in staining buffer (PBS supplemented with 2% FBS).The cells were then incubated on ice for 20 min in fluorescein-labeled streptavidin (BD Biosciences, Franklin Lakes, NJ; #554060), washed twice in PBS, stained with 7AAD (viability stain) for 15 min, and analyzed by flow cytometry using BD Accuri C6 software (BD Biosciences, Franklin Lakes, NJ). FIG. 6E shows the flow cytometry data, corroborating that the THP-1 macrophages were FRB+ and therefore suitable for the in vitro study of Compound 1B and other studies described herein. [000480] FIG. 6F confirms that Compound 1B remained stable during the incubation period, which was 37 °C in the culture medium. In fact, Compound 1B maintained its original structure after 48 hours of incubation. Example 4 Bleomycin-induced pulmonary fibrosis and in vivo reprogramming of anti-inflammatory macrophages [000481] Studies have also been conducted to determine if Petition 870250096077, dated 10 / 21 / 2025, pp. 258 / 378 254 / 297 macrophages in lungs with pulmonary fibrosis could be specific targets for folate-linked drugs in vivo. After testing multiple protocols for inducing pulmonary fibrosis in mice, a protocol was selected in which 0.75 mg / kg of bleomycin (BM) is instilled into the lungs of C57BL / 6 mice via a tracheal incision, allowing the mice to progress through the inflammatory and fibrotic stages of fibrosis before the start of therapy. (The BM model is widely considered useful in terms of enabling mechanistic investigations relevant to fibrogenesis in an in vivo context.) [000482] As shown in FIGS. 7A-7D, mice treated with this protocol typically exhibit fibrosis on day 7 after BM treatment, and this incipient fibrosis evolves into severe fibrosis on day 14. The progression of the pathology continues for another 2 to 5 days before beginning to resolve spontaneously on the 21st day. [000483] More specifically, eight-week-old male C57BL6 mice from Charles River (mean weight 22 g ± 25 g) were housed in pathogen-free conditions at room temperature (22 °C) under a 12-hour light-dark cycle. Mice were fed folate-deficient diet (Envigo Teklad Global Rat Food Pellets) for 1 week prior to BM or PBS instillation. Fresh water and folate-deficient diet were freely available. All animal procedures were approved by the Purdue Animal Care and Use Committee, in accordance with National Institutes of Health guidelines. [000484] Next, the mice were anesthetized with ketamine / xylazine and their necks were shaved with depilatory lotion and then sterilized with 70% alcohol. A small incision was made in the neck to visualize the trachea. The mice were positioned at a 75-degree angle and injected intratracheally. Petition 870250096077, dated 10 / 21 / 2025, pp. 259 / 378 255 / 297 with 100 pL of sterile PBS or BM (Cayman Chemicals, Ann Arbor, MI; #13877) dissolved in PBS (0.75 mg / kg) using a 1 cc syringe with a 26 G needle. Body weights were monitored on alternate days throughout the experiment. [000485] To evaluate whether anti-inflammatory pulmonary macrophages in these mice can be specific targets of folate-linked drugs, 10 days after instillation, 10 nmol (for in vivo imaging) or 100 nmol (for in vivo labeling) of a folate-linked near-infrared fluorescent dye (OTL38), with or without a 200-fold excess of FAglucosamine (an OTL38 competitor), were injected into the tail veins of BM-treated mice, and dye uptake in major organs was assessed. [000486] After 2 hours, the mice were sacrificed by CO2 asphyxiation, and an incision in the skin, from the abdomen to the neck, was immediately made to expose the lungs and trachea. A small cut in the upper trachea was then made for the insertion of a blunt 22-gauge needle, and a nylon thread was tied around the trachea to seal it around the needle. The trachea (containing the inserted needle), lungs, and heart were then removed en masse, carefully cutting the connective tissue below the lungs, and the bronchus of the left lung was clipped with a Dieffenbach vessel clip. The right lung was injected with PBS and aspirated 3 times with a 1 ml syringe, and the recovered wash fluid was stored on ice. [000487] Bronchoalveolar lavage fluid (BAL) was then analyzed to determine how the target TLR7 agonist acts. BALF samples were centrifuged at 1500 rpm for 5 min at 4 °C and the supernatant was aliquoted and stored at -80 °C for cytokine / chemokine analyses. Cell pellets were resuspended and cultured in RPMI 1640 medium. Petition 870250096077, dated 10 / 21 / 2025, pp. 260 / 378 256 / 297 pre-warmed for 2 hours and then washed 3 times with pre-warmed PBS before collection for qPCR assay. The right lung was then tied with nylon thread and used for subsequent analysis of hydroxyproline content. The left lung was inflated with 1 ml of PBS using the inserted syringe and transferred to 10% formalin solution for subsequent histological analyses. [000488] The right lung lobes collected above were weighed, placed in a hermetically sealed container (Supelco Inc., Bellefonte, PA; #27003) and hydrolyzed with 6N HCl (10 ml / g, v / w) in a sand bath at 120 °C for 3.5 hours. The hydrolyzed solution was cooled to 4 °C for 15 minutes and transferred to a 1.5 ml Eppendorf tube before centrifugation at 12,000 μm for 15 minutes at 4 °C. The supernatant was carefully collected, aliquoted, and used for hydroxyproline (HYP) analysis. [000489] For subsequent HYP analysis, 10 µl of the sample were transferred to a 96-well plate and neutralized with 10 µl of 5.3 M sodium hydroxide solution. Isopropanol (40 µl) was then added to each well, followed by 20 µl of oxidation buffer, and the mixture was incubated on a shaker at room temperature for 5 min. The analytical reagent (260 µl) was added, and the plate was incubated on a shaker at room temperature for 30 seconds and immediately incubated at 60 °C for 25 min. Absorbance was measured at 560 nm (As6o) at 15 min. All reagents were prepared according to a previously reported protocol. [000490] For histological analysis of lung sections, fixed lungs (see above) were embedded in paraffin, sectioned, and stained with hematoxylin-eosin (H&E), Masson's trichrome, or F3 (anti-mouse FRB antibody). Tissue sections were examined blindly by a licensed pathologist. More than 90 x 106 cells were quantified per section using the Aperio-Image Scope (Leica Biosystems, Petition 870250096077, dated 10 / 21 / 2025, pp. 261 / 378 257 / 297 Wetzlar, DE). [000491] CCL18 and IL-1β were quantified in THP-1 induced cell supernatants using a human DuoSet ELISA Development System (R&D Systems Europe, Abingdon, UK: #DY39405) and a human IL-1 beta ELISA Kit (Thermo Fisher Scientific, Waltham, MA: #BMS224-2), as described by the manufacturers. LBA samples were analyzed for IFN-γ in mice using ELISA MAX™ Deluxe (BioLegend, San Diego, CA; #430804). [000492] Finally, for in vivo folate imaging studies, the major organs (heart, lung, spleen, liver, small intestine, large intestine, and kidney) were resected and imaged using an AMI Live imager (Spectral Instruments Imaging, Tucson, AZ). For in vivo folate receptor labeling studies, mouse lungs were collected immediately after euthanasia, digested with a lung dissociation kit (Miltenyi Biotec, Bergisch Gladbach, DE; #130-098-427) as described by the gentleMACS Octo Dissociator with Heathers (Miltenyi Biotec, Bergisch Gladbach, DE: #130-096-427) as described in the manual, and filtered through a 70 μm cell filter (Miltenyi Biotec, Bergisch Gladbach, DE: #130-098-462).Cells collected in the filtrate were depleted of erythrocytes by lysis with ammonium sulfate, washed twice in cold PBS, and labeled for 30 minutes on ice with antibodies to the desired macrophage markers (FITC-CD1 lb, BioLegend, San Diego, CA; #101205; FE-F4 / 80, BioLegend, San Diego, CA: #123109). Labeled macrophages were then washed twice in PBS, stained with 7AAD (viability stain) for 15 minutes, and analyzed by flow cytometry using BD Accuri C6 Soft™ (BD Biosciences, San Jose, CA). [000493] As shown in FIG. 7A (top panel), the untreated lungs (control column with PBS) and the lungs treated with BM in Petition 870250096077, dated 10 / 21 / 2025, pp. 262 / 378 258 / 297 day 7 exhibit a similar high density of alveoli interconnected by a minimal extracellular matrix. In contrast, on day 14 after BM instillation, the size and frequency of air sacs decreased significantly and the density of the extracellular matrix visibly increased, suggesting the development of significant fibrosis in the treated mice. By day 21, the pathology in this model had already begun to resolve spontaneously, with many mice recovering from the BM-induced trauma by day 35. [000494] Evidence of inflammation development on day 7 is observed from the infiltration of FRB-expressing macrophages (see lower panel of FIG. 7A and quantification in FIG. 7B), which are almost completely absent in healthy lungs but continue to accumulate until day 14 in lungs exposed to MO.Furthermore, F3 staining showed significant FRB expression in the IPF lung (mainly in the interstitial space), as previously reported in the literature (FIG. 7A). FRB expression was restricted to the inflamed lung (both in the IPF patient and in the induced MO, but not in the healthy lung). Additionally, FRB-expressing macrophages were observed in mouse lungs on day 7 after BM administration, with peak expression on day 14 (FIG. 7B). These results corroborated the previously reported FRB expression in activated macrophages in the inflamed lung. [000495] That these FRB-expressing macrophages can be targets of folate-bound molecules was then demonstrated by the accumulation of OTL38, a fluorescent dye targeting folate, in the lungs of BM-treated but unhealthy mice after injection into the tail vein. As shown in FIG. 7B, OTL38 fluorescence was observed only in the kidneys of healthy mice (i.e., their main site of excretion), with little or no uptake in others. Petition 870250096077, dated 10 / 21 / 2025, pp. 263 / 378 259 / 297 fabrics. [000496] FIGS. 7C and 7D show IHC FRB staining of human lung tissue with FPI (FIG. 7C) and healthy human lung tissue (FIG. 7D). Male C57BL / 6 mice were fed a folate-deficient diet for 1 week prior to BM or PBS instillation. Ten days after instillatio...

Claims

1. Treatment Method, for an individual with cancer, the method characterized in that it comprises: administering a first therapy to an individual, the first therapy comprising: at least one pharmaceutically acceptable compound or salt or hydrate thereof comprising a radical of an immune modulator linked, by means of a ligand, to a folate ligand or functional fragment or analogue thereof, or a composition comprising at least one compound and one or more pharmaceutically acceptable carriers, adjuvants, diluents, excipients and / or vehicles, or combinations thereof; and administering a second therapy to the individual, the second therapy comprising one or more immune checkpoint inhibitors.

2. Treatment Method, according to Claim 1, characterized in that the administration of the second therapy to the individual further comprises the administration of a therapeutically effective amount of one or more immune checkpoint inhibitors.

3. Treatment Method, according to Claim 1, characterized in that the administration of at least one compound of the first therapy reprograms the individual's M2-type macrophages to M1-type macrophages and increases the potency of one or more immune checkpoint inhibitors of the second therapy relative to the baseline potency of one or more immune checkpoint inhibitors. Petition 870250084749, dated 09 / 19 / 2025, pp. 268 / 297 2 / 19 4. Treatment Method, according to Claim 1, characterized in that the immunomodulatory radical or pharmaceutically acceptable salt or hydrate thereof comprises a Toll-tike receptor (TLR) 3 agonist, a TLR 7 agonist, a TLR 8 agonist, a TLR 9 agonist or a TLR 7 / 8 agonist.

5. Treatment Method according to Claim 1, characterized in that at least one compound has the formula: or is a pharmaceutically acceptable salt or hydrate thereof.

6. Treatment Method, according to Claim 1, characterized in that at least one compound has the following formula: Petition 870250084749, dated 19 / 09 / 2025, p. 269 / 297 3 / 19 or is a pharmaceutically acceptable salt or hydrate thereof.

7. Treatment Method, according to any one of Claims 1 to 4, characterized in that the immunomodulator radical is or comprises a TLR agonist of Formula X or XX, or is a pharmaceutically acceptable salt or hydrate of Formula X or XX: 195 (XX) where, in Formulas X and XX: Ri is -NH2 or -NH-Rix, Petition 870250084749, dated 19 / 09 / 2025, p. 270 / 297 4 / 19 R2 is an H, an alkyl, an alkenyl, an alkynyl, an alicyclic, an aryl, a biaryl, a heteroaryl, -NH-R2x, -O-R2x, -S-, ,R2X —N R2Y R2X R2Y OR, a non-aromatic mono- or bicyclic heterocycle of 3 to 10 members, containing N, where: in Formula X, R3 is -OH, -SH, -NH2 or -NH-Rix; in Formula XX, X is a CH or an N; and each of Rix, R2x and R2y is selected independently from the group consisting of an H, an alkyl, an alkenyl, an alkynyl, an alicyclic, an aryl, a biaryl and a heteroaryl.

8. Treatment Method, according to Claim 1, characterized in that at least one compound of the first therapy comprises: Formula (2-1) or is a pharmaceutically acceptable salt or hydrate thereof, wherein, in Formula 2-1: R1, R3, R4 and R5 are each independently a Petition 870250084749, dated 19 / 09 / 2025, page. 271 / 297 5 / 19 hydrogen (H), an alkyl, an alkoxyl, an alkenyl, an alkynyl, an alicyclic, an aryl, a biaryl, a halo, a heteroaryl, -COR2x, OHρ, (p = 0-30) Ar2· : R2y R2* R2 is an H, -OH, -NH2, -NHR2x, N3, -NH-CH2-NH2, -CONH2, Λ / p?x nArPx zn' SO2NH2, -NH-CS-NH2, A, OR A · ny Y is a point of attachment to the ligand of at least one compound and comprises an H, -OH, NH2, -NHR2x, -O-R2x, -SO-R2x, -SH, -SO3H, -N3, -CHO, -COOH, -CONH2, COSH, -COR2x, -SO2NH2, alkenyl, alkynyl, alkoxyl, -NH-CH2-NH2, CONH2, -SO2NH2, -NH-CS-NH2, Z / ., Z R2x , or A R2x ; b” A ,νΎ R2y R2y where: tr R? / each of R2x and R2y is independently selected from the group consisting of H, -OH, -CH2-OH, -NH2, -CH2-NH2, -COOMe, COOH, -CONH2, -COCH3, alkyl, alkenyl, alkynyl, alicyclic, aryl, biaryl and heteroaryl, and each R2z is independently selected from the group consisting of -NH2, -NR2ciR2ci', -O-R2ci, -SO-R2ci and -COR2ci, where each of R2q and R2q' is independently alkyl or H; and is a 3 to 10 membered N-containing heterocycle that is non-aromatic, mono- or bicyclic; H, halogen or an optionally substituted alkyl; and Petition 870250084749, dated 19 / 09 / 2025, page.

9. Treatment Method, according to any one of Claims 1 to 6 and 8, characterized in that the individual is suffering from, or is at risk of suffering from, cancer or a recurrence of cancer, and the first therapy administration step further comprises administering or applying to the individual a therapeutically effective amount of at least one pharmaceutically acceptable compound or salt or hydrate thereof.

10. Treatment Method, according to any one of Claims 1 to 6 and 8, characterized in that the first therapy is administered to the individual intravenously, orally, intramuscularly, intraperitoneally, topically, or by inhalation.

11. Treatment Method, according to Claim 3, characterized in that the individual's M2-type macrophages are myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), or both MDSCs and TAMs.

12. Treatment Method, according to any one of Claims 1 to 6, 8 and 11, characterized in that the individual has tumors positive for programmed death ligand 1 (PD-L1), programmed death 1 (PD-1) or cytotoxic T lymphocyte-associated antigen 4 (CTLA-4).

13. Treatment Method, according to any one of Claims 1 through 6, 8 and 11, characterized in that it is performed to treat a cancer recurrence in the individual or resistance to checkpoint blockade therapy in the individual. Petition 870250084749, dated 09 / 19 / 2025, pp. 273 / 297 7 / 19 14. Treatment Method, according to any one of Claims 1 to 6, 8 and 11, characterized in that the individual is a human, a rat or any other mammal.

15. Treatment Method, according to Claim 1, characterized in that one or more immune checkpoint inhibitors of the second therapy each comprise a small molecule or other agent that disrupts an immune checkpoint of an individual's cell.

16. Treatment Method, according to any one of Claims 1 to 6, 8, 11 and 15, characterized in that one or more immune checkpoint inhibitors of the second therapy each comprise a small molecule or other agent that disrupts an immune checkpoint of an individual's cell.

17. Treatment Method, according to any one of Claims 1 to 6, 8, 11 and 15, characterized in that one or more second-therapy immune checkpoint inhibitors are each independently selected from the group consisting of pembrolizumab, nivolumab, ipilimumab, cemiplimab, atezolizumab, avelumab, durvalumab, pidilizumab, monoclonal antibody MEDI0680, monoclonal antibody REGN2810 or fusion protein AMP-224 targeting PD-1, ociperlimab, islelizumab, a combination of ociperlimab and islelizumab, BMS-936559 / MDX-1105, MPDL3280A / RG7446 / atezolizumab, MSB0010718C / avelumab or MEDI4736 / durvalumab, tiragolumab, zimberelimab, tremelimumab, relatlimab, monoclonal antibody IMP321, nivolumab, etigilimab, domvanalimab, tiragolumab (RG6058), vibostolimab, avelumab and durvalumab. Petition 870250084749, dated 09 / 19 / 2025, pp. 274 / 297 8 / 19 18. Treatment Method, according to any one of Claims 1 to 6, 8, 11 and 15, characterized in that the immunomodulator radical comprises a TLR agonist with the following formula: wherein: R1 is an amine group, R2 is a single -NH- bond, R3 is an H, an alkyl, a hydroxyl group or any other substituted group thereof, X is a CH2, NH, O or S, and the ligand is attached to R1, R2 or R3.

19. Treatment Method, according to any one of Claims 1 to 6, 8, 11 and 15, characterized in that the ligand is a non-releasable ligand.

20. Treatment Method, according to any one of Claims 1 to 6, 8, 11 and 15, characterized in that the ligand is a releasable ligand.

21. Treatment Method, according to any of Claims 1 to 6, 8, 11 and 15, characterized in that the binder of Petition 870250084749, dated 09 / 19 / 2025, p. 275 / 297 9 / 19, at least one pharmaceutically acceptable compound or salt or hydrate of the first therapy comprises a polyethylene glycol (PEG) binder or a PEG-derived binder and is a non-releasable binder.

22. Treatment Method, according to any one of Claims 1 to 6, 8, 11 and 15, characterized in that one or more second-therapy immune checkpoint inhibitors inhibit an immune checkpoint of a selected cell from a group consisting of PD-1, PD-L1, CTLA-4, T cell activation domain V Ig suppressor (VISTA), lymphocyte activator 3 (LAG3), T cell immunoglobulin-containing mucin domain protein 3 (TIM3), T cell immunoreceptor with Ig and ITIM domains (TIGIT), programmed death ligand 2 (PD-L2), indoleamine 2,3-deoxygenase (IDO), arginase-1 (AGR1), B7 family inhibitory ligand B7-H3 (B7-H3), B7 family inhibitory ligand B7-H4 (B7-H4), 2B4 (cluster of differentiation 244), B and T lymphocyte attenuator (BTLA), adenosine A2A receptor (A2aR) and / or a member of the killer cell immunoglobulin-like receptor (KIR) family, such as KIRs and C-type lectin receptors,and signal transducer and transcription activator (STAT3).

23. Treatment Method, according to any one of Claims 1 to 6, 8, 11 and 15, characterized in that the first and second therapies are administered simultaneously or sequentially in any order.

24. Treatment Method, according to any of Claims 1 to 23, characterized by the administration of at least one pharmaceutically acceptable compound or salt or hydrate of the first active antitumor cell therapy or an anti-inflammatory signaling cascade in the individual.

25. A method for increasing the potency of one or more immune checkpoint inhibitors administered to an individual, characterized in that it comprises: administering to the individual one or more pharmaceutically acceptable compounds or salts or hydrates thereof, comprising a radical of an immune modulator linked, via a ligand, to a folate ligand or functional fragment or analogue thereof; and placing a target cell of the individual in contact with one or more pharmaceutically acceptable compounds or salts or hydrates to reprogram the individual's M2-type macrophages into M1-type macrophages.

26. Potency Enhancement Method, according to Claim 25, characterized in that the immunomodulator radical is a Toll-like receptor (TLR) 3 agonist, a TLR 7 agonist, a TLR 8 agonist, a TLR 9 agonist, or a TLR 7 / 8 agonist.

27. Potency Enhancement Method, according to Claim 25, characterized in that the immunomodulator radical is or comprises a TLR7 agonist and the ligand is a releasable ligand.

28. Potency Enhancement Method, according to Claim 25, characterized in that the immunomodulator radical is or comprises a TLR7 agonist and the ligand is a non-releasable ligand.

29. Potency Enhancing Method, according to Claim 25, characterized in that one or more compounds is or comprises the formula: or is a pharmaceutically acceptable salt or hydrate thereof.

30. A method for increasing potency according to Claim 25 or Claim 26, characterized in that the ligand is a non-releasable ligand.

31. A method of increasing potency, according to any one of Claims 25 to 27 and 29, characterized in that the cancerous disease state comprises a recurrence of the cancer.

32. Potency Enhancement Method, according to Claim 24, characterized in that the antitumor cells are T cells, macrophages, or T cells and macrophages.

33. Combination, for use in the treatment of cancer in an individual, characterized in that it comprises: a first medicinal product comprising: at least one pharmaceutically acceptable compound or salt or hydrate thereof comprising a radical of an immune modulator linked, by means of a ligand, to a folate ligand or functional fragment or analogue thereof, wherein the radical of the immune modulator targets a pattern recognition receptor or a damage-associated molecular pattern (DAMP), or a composition comprising at least one pharmaceutically acceptable compound or salt or hydrate thereof and one or more pharmaceutically acceptable carriers, adjuvants, diluents, excipients and / or vehicles; a second medicinal product comprising one or more immune checkpoint inhibitors.

34. Combination, according to Claim 33, characterized in that the immunomodulator radical comprises a Toll-like receptor (TLR) 3 agonist, a TLR 7 agonist, a TLR 8 agonist, a TLR 9 agonist, or a TLR 7 / 8 agonist.

35. Combination, according to Claim 33, characterized in that at least one compound has the following formula: or is a pharmaceutically acceptable salt or hydrate thereof. Petition 870250084749, dated 19 / 09 / 2025, p. 279 / 297 13 / 19 36. Combination according to Claim 33, characterized in that the radical of the immune modulator comprises a TLR agonist of Formula X or XX, or is a pharmaceutically acceptable salt or hydrate of Formula X or XX: (X) (XX) wherein, in Formulas X and XX: Ri is -NH2 or -NH-Rix, Ra is an H, an alkyl, an alkenyl, an alkynyl, an alicyclic, p R is an aryl, a biaryl, a heteroaryl, NH-R2X, -O-R2x, -S-R2X,_2X or_N'%, 2X _NY R2y , and V is a non-aromatic mono- or bicyclic heterocycle containing N of 3 to 10 members, wherein: in Formula X, R3 is -OH, -SH, -NH2 or -NH-Rix; Petition 870250084749, dated 09 / 19 / 2025, p. 280 / 297 14 / 19 in Formula XX, X is a CH or an N; and each of Rix, R2x and R2y is independently selected from the group consisting of an H, an alkyl, an alkenyl, an alkynyl, an alicyclic, an aryl, a biaryl and a heteroaryl.

37. Combination according to Claim 33, characterized in that at least one compound of the first medicinal product comprises: Formula (2-1) or is a pharmaceutically acceptable salt or hydrate thereof, wherein, in Formula 2-1: R1, R3, R4, and R5 are each independently a hydrogen (H), an alkyl, an alkoxyl, an alkenyl, an alkynyl, an alicyclic, an aryl, a biaryl, a halo, a heteroaryl, -COR2x, , , or <P’°'30) R2y R2y R2 é um H, -OH, -NH2, -NHR2x, N3, -NH-CH2-NH2, -CONH2, -so2nh2, -nh-cs-nh2, An^R2x , ou An'r2x ; R2y R2y Y é um ponto de ligação ao ligante e / ou ao ligante de direcionamento de pelo menos um composto e compreende um H, -OH, NH2, -NHR2x, -0-R2x, -SO-R2x, -sh, -so3h, -N3, -CHO, -COOH, -CONH2, Petição 870250084749, de 19 / 09 / 2025, pág.281 / 297 15 / 19 COSH, -COR2x, -SO2NH2, alkenyl, alkynyl, alkoxyl, -NH-CH2-NH2, conh2, -so2nh2, -NH-CS-NH2, Z / , bZ r2x where: psy □ 2x n'r r2V , OR each of R2x and R2y is independently selected from the group consisting of H, -OH, -CH2-OH, -NH2, -CH2-NH2, -COOMe, COOH, -CONH2, -COCH3, alkyl, alkenyl, alkynyl, alicyclic, aryl, biaryl and heteroaryl, and each R2z is independently selected from the group consisting of -NH2, -NR2 <iR2ci’, -O-R2ci, -SO-R2ci e -COR2ci, em que cada um de R2q e R2q’ é independentemente alquil ou H; é um heterociclo contendo N de 3 a 10 membros que é não aromático, mono ou bicíclico; em que, na Fórmula 2-1, cada um de X1, X2 e X3 é independentemente CR^ ou N, e cada R^ é independentemente H, halogênio ou um alquil opcionalmente substituído; em que, na Fórmula 2-1, n é 0-30 e m é 0-4.

38. Combination, according to Claim 33, characterized in that the immunomodulator radical of the first medicinal product comprises a TLR agonist with the following formula or a pharmaceutically acceptable salt thereof: Petition 870250084749, dated 19 / 09 / 2025, p. 282 / 297 16 / 19 where: R1 is an amine group, R2 is a single -NH- linkage, R3 is an H, an alkyl, a hydroxyl group or any other substituted group thereof, X is a CH2, NH, O, or S, and the ligand is attached to R1, R2 or R3.

39. Combination, according to Claim 33, characterized in that at least one component of the first medicinal product is or comprises the formula: or is a pharmaceutically acceptable salt or hydrate thereof.

40. Combination, according to Claim 33, characterized in that the linker of at least one pharmaceutically acceptable compound or salt or hydrate of the first medicinal product is a releasable linker. Petition 870250084749, dated 19 / 09 / 2025, pp. 283 / 297 17 / 19 41. Combination, according to Claim 33, characterized in that the linker of at least one pharmaceutically acceptable compound or salt or hydrate of the first medicinal product is a non-releasable linker.

42. Combination, according to Claim 33, characterized in that the linker of at least one pharmaceutically acceptable compound or salt or hydrate of the first medicinal product comprises a polyethylene glycol (PEG) linker or a PEG-derived linker and is a non-releasable linker.

43. Combination, according to any of Claims 33 to 42, characterized in that the individual has a tumor positive for programmed death ligand 1 (PD-L1), programmed death 1 (PD-1) or cytotoxic T lymphocyte-associated antigen 4 (CTLA-4).

44. Combination, according to Claim 33, characterized in that one or more immune checkpoint inhibitors of the second drug comprise a small molecule or other agent that disrupts an immune checkpoint of an individual's cell.

45. Combination, according to any one of Claims 33 to 42 and 44, characterized in that one or more checkpoint inhibitors of the second drug are each independently selected from the group consisting of pembrolizumab, nivolumab, ipilimumab, cemiplimab, atezolizumab, avelumab, durvalumab, pidilizumab, MEDI-0680 monoclonal antibody, REGN2810 monoclonal antibody or AMP-224 fusion protein targeting PD-1, ociperlimab, islelizumab, a combination of ociperlimab and islelizumab, BMS-936559 / MDX-1105, Petition 870250084749, dated 09 / 19 / 2025, p. 284 / 297 18 / 19 MPDL3280A / RG7446 / atezolizumab, MSB0010718C / avelumab or MEDI4736 / durvalumab, tiragolumab, zimberelimab, tremelimumab, relatlimab, monoclonal antibody IMP321, nivolumab, etigilimab, domvanalimab, tiragolumab (RG6058), vibostolimab, avelumab and durvalumab.

46. ​​Combination, according to any one of Claims 33 to 42 and 44, characterized in that one or more immune checkpoint inhibitors of the second drug are one or more agents that bind to or inhibit an immune checkpoint of a selected cell from a group consisting of PD-1, PD-L1, CTLA-4, T cell activation domain V Ig suppressor (VISTA), lymphocyte activator 3 (LAG3), T cell immunoglobulin-containing mucin domain protein 3 (TIM3), T cell immunoreceptor with Ig and ITIM domains (TIGIT), programmed death ligand 2 (PD-L2), indoleamine 2,3-deoxygenase (IDO), arginase-1 (AGR1), B7 family inhibitory ligand B7-H3 (B7-H3), B7 family inhibitory ligand B7-H4 (B7H4), 2B4 (cluster of differentiation). 244), B and T lymphocyte attenuator (BTLA), adenosine A2A receptor (A2aR) and / or a member of the killer cell immunoglobulin-like receptor (KIR) family,such as KIRs and C-type lectin receptors, and signal transducer and activator of transcription (STAT3).

47. Combination, according to any of Claims 33 to 42 and 44, characterized in that the cancer comprises a cold tumor, a hot tumor, or an immune desert tumor.

48. Combination, according to any of Claims 33 to 47, characterized in that it is used to increase the potency of one or more immune checkpoint inhibitors administered to an individual with cancer and / or to treat cancer.

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