Methods for Treating Cancer

Abstract

Provided herein are methods of treating a subject, e.g., a subject having cancer, the method comprising administering a therapeutically effective amount of a STING antagonist, or a pharma- ceutically acceptable salt, solvate, or co-crystal thereof, to a subject identified as having (I) cancer cells having one or both of: (i) a decreased level and / or activity of TREX1, and (ii) an increased cGAS / STING signaling pathway activity, e.g., compared to a reference level, and / or (II) an elevated level of cGAMP in a serum sample or tumor sample obtained from the subject, e.g., compared to a reference level.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 129,202, filed December 22, 2020, which is incorporated by reference in its entirety.

[0002] Technical Field The disclosure relates, in part, to a method of treating a subject, such as a subject with cancer, comprising administration of a STING antagonist. [Background technology]

[0003] background The cGAS / STING (cyclic GMP-AMP synthase / stimulator of interferon genes) pathway is a component of the inflammatory signaling pathway. When DNA is present in the cytosol of a cell, cGAS binds to it to generate 2'-5' cyclic GMP-AMP (cGAMP). STING is activated by cGAMP to induce phosphorylation and nuclear translocation of interferon (IFN) regulatory factors (IRFs). As transcription factors, IRFs control the expression of genes, including type I IFNs, which control the activity of the immune system.

[0004] The presence of DNA in the cytosol of a cell can be the result of an infection. In some cases, the presence of DNA in the cytosol of a cell can be the result of DNA damage in the nucleus of the cell or in the mitochondria of the cell. In some cases, cytosolic DNA is degraded or modified by enzymes to prevent activation of the cGAS / STING pathway. One such enzyme is TREX1 (3' repair exonuclease 1; also known as DNaseIII). Summary of the Invention

[0005] overview The present disclosure is based on the discovery that cancer cells having decreased levels and / or activity of TREX1 and / or increased cGAS / STING signaling pathway activity and / or elevated levels of cGAMP are more sensitive to treatment with a STING antagonist or cGAS inhibitor, for example, compared to cells that do not have decreased levels and / or activity of TREX1 and / or increased cGAS / STING signaling pathway activity.

[0006] Provided herein is a method of treating a subject in need thereof, comprising: (a) identifying a subject having (I) cancer cells having one or both of: (i) a decreased level and / or activity of TREX1, and (ii) an increased cGAS / STING signaling pathway activity, compared to a reference level; and (b) administering to the identified subject a treatment comprising a therapeutically effective amount of a STING antagonist, or a pharma- ceutically acceptable salt, solvate, or co-crystal thereof, wherein the STING antagonist is a compound of any one of Formulas I-XXIV (e.g., Formulas XI-XV) or Formulas M1-M6 (e.g., Formulas M3-M6), or a compound set forth in Table C1.

[0007] Also provided herein is a method of treating a subject in need thereof, comprising: administering to a subject identified as having (I) cancer cells having one or both of: (i) a decreased level and / or activity of TREX1, and (ii) an increased cGAS / STING signaling pathway activity, and / or (II) an elevated level of cGAMP in a serum sample or tumor sample obtained from the subject, compared to a reference level, a treatment comprising a therapeutically effective amount of a STING antagonist, or a pharma- ceutically acceptable salt, solvate, or co-crystal thereof, wherein the STING antagonist is a compound of any one of Formulas I-XXIV (e.g., Formulas XI-XV) or Formulas M1-M6 (e.g., Formulas M3-M6), or a compound set forth in Table C1.

[0008] Also provided herein is a method of selecting a treatment for a subject in need thereof, comprising: (a) identifying a subject having (I) cancer cells having one or both of (i) a decreased level and / or activity of TREX1, and (ii) an increased cGAS / STING signaling pathway activity, and / or (II) an elevated level of cGAMP in a serum sample or tumor sample obtained from the subject, compared to a reference level; and (b) selecting for the identified subject a treatment comprising a therapeutically effective amount of a STING antagonist, or a pharma- ceutically acceptable salt, solvate, or co-crystal thereof, wherein the STING antagonist is a compound of any one of Formulas I-XXIV (e.g., Formulas XI-XV) or Formulas M1-M6 (e.g., Formulas M3-M6), or a compound set forth in Table C1.

[0009] Also provided herein is a method of selecting a treatment for a subject in need thereof, comprising: selecting for a subject identified as having (I) cancer cells having one or both of: (i) a decreased level and / or activity of TREX1, and (ii) an increased cGAS / STING signaling pathway activity, and / or (II) an elevated level of cGAMP in a serum sample or tumor sample obtained from the subject, compared to a reference level, a treatment comprising a therapeutically effective amount of a STING antagonist, or a pharma- ceutically acceptable salt, solvate, or co-crystal thereof, wherein the STING antagonist is a compound of any one of Formulas I-XXIV (e.g., Formulas XI-XV) or Formulas M1-M6 (e.g., Formulas M3-M6), or a compound set forth in Table C1.

[0010] Also provided herein is a method of selecting a subject for treatment, the method comprising: (a) identifying a subject having (I) cancer cells having one or both of (i) a decreased level and / or activity of TREX1, and (ii) an increased cGAS / STING signaling pathway activity, and / or (II) an elevated level of cGAMP in a serum sample or a tumor sample obtained from the subject, compared to a reference level; and (b) selecting the identified subject for treatment with a therapeutically effective amount of a STING antagonist, or a pharma- ceutically acceptable salt, solvate, or co-crystal thereof, wherein the STING antagonist is a compound of any one of Formulas I-XXIV (e.g., Formulas XI-XV) or Formulas M1-M6 (e.g., Formulas M3-M6), or a compound set forth in Table C1.

[0011] Also provided herein is a method of selecting a subject for participation in a clinical trial, comprising: (a) identifying a subject having (I) cancer cells having one or both of: (i) a decreased level and / or activity of TREX1, and (ii) an increased cGAS / STING signaling pathway activity, and / or (II) an elevated level of cGAMP in a serum sample or a tumor sample obtained from the subject, compared to a reference level; and (b) selecting the identified subject for participation in a clinical trial comprising administration of a treatment comprising a therapeutically effective amount of a STING antagonist, or a pharma- ceutically acceptable salt, solvate, or cocrystal thereof, wherein the STING antagonist is a compound of any one of Formulas I-XXIV (e.g., Formulas XI-XV) or Formulas M1-M6 (e.g., Formulas M3-M6), or a compound set forth in Table C1.

[0012] Also provided herein is a method of selecting a subject for participation in a clinical trial comprising the steps of: selecting a subject identified as having (I) cancer cells having one or both of: (i) a decreased level and / or activity of TREX1, and (ii) an increased cGAS / STING signaling pathway activity, and / or (II) an elevated level of cGAMP in a serum sample or tumor sample obtained from the subject, compared to a reference level, for participation in a clinical trial comprising administration of a treatment comprising a therapeutically effective amount of a STING antagonist, or a pharma- ceutically acceptable salt, solvate, or cocrystal thereof, wherein the STING antagonist is a compound of any one of Formulas I-XXIV (e.g., Formulas XI-XV) or Formulas M1-M6 (e.g., Formulas M3-M6), or a compound set forth in Table C1.

[0013] Also provided herein is a method of predicting a subject's responsiveness to a STING antagonist, comprising: (a) determining that the subject has cancer cells having one or both of: (i) a decreased level and / or activity of TREX1, and (ii) an increased level of cGAS / STING signaling pathway activity, and / or (II) an elevated level of cGAMP in a serum sample or tumor sample obtained from the subject, compared to a reference level; and (b) determining in step (a) that the subject has cancer cells having one or both of: (I) (i) a decreased level and / or activity of TREX1, and (ii) an increased level of cGAS / STING signaling pathway activity, and / or (II) an elevated level of cGAMP in a serum sample or tumor sample obtained from the subject, compared to a reference level. Identifying a subject determined to have an elevated level of cGAMP in a serum sample or tumor sample obtained from the subject as having an increased likelihood of responding to treatment with a STING antagonist, wherein the STING antagonist is a compound of any one of Formulas I-XXIV (e.g., Formulas XI-XV) or Formulas M1-M6 (e.g., Formulas M3-M6), or a compound set forth in Table C1.

[0014] Also provided herein is a method of predicting a subject's responsiveness to a STING antagonist, comprising: identifying a subject determined to have (I) cancer cells having one or both of (i) a decreased level and / or activity of TREX1, and (ii) an increased cGAS / STING signaling pathway activity, and / or (II) an elevated level of cGAMP in a serum sample or tumor sample obtained from the subject, compared to a reference level, as having an increased likelihood of responding to treatment with a STING antagonist, wherein the STING antagonist is a compound of any one of Formulas I-XXIV (e.g., Formulas XI-XV) or Formulas M1-M6 (e.g., Formulas M3-M6), or a compound set forth in Table C1.

[0015] In some embodiments of any of the methods described herein, the subject is identified as having cancer cells with decreased levels and / or activity of TREX1. In some embodiments of any of the methods described herein, the subject is identified as having cancer cells with increased cGAS / STING signaling pathway activity. In some embodiments of any of the methods described herein, the subject is identified as having cancer cells with both (i) decreased levels and / or activity of TREX1 and (ii) increased cGAS / STING signaling pathway activity.

[0016] In some embodiments of any of the methods described herein, the subject is identified as having cancer cells with a decreased level of TREX1. In some embodiments of any of the methods described herein, the level of TREX1 is a level of TREX1 protein in the cancer cells. In some embodiments of any of the methods described herein, identifying the subject as having cancer cells with a decreased level of TREX1 comprises detecting a decreased level of TREX1 protein in the cancer cells. In some embodiments of any of the methods described herein, the level of TREX1 is a level of TREX1 mRNA in the cancer cells. In some embodiments of any of the methods described herein, identifying the subject as having cancer cells with a decreased level of TREX1 comprises detecting a decreased level of TREX1 mRNA in the cancer cells.

[0017] In some embodiments of any of the methods described herein, the decreased level and / or activity of TREX1 is a result of TREX1 gene loss in the cancer cells. In some embodiments of any of the methods described herein, the TREX1 gene loss is loss of one allele of the TREX1 gene. In some embodiments of any of the methods described herein, the TREX1 gene loss is loss of both alleles of the TREX1 gene. In some embodiments of any of the methods described herein, identifying the subject as having cancer cells with decreased level and / or activity of TREX1 comprises detecting TREX1 gene loss in the cancer cells.

[0018] In some embodiments of any of the methods described herein, the decreased level and / or activity of TREX1 is the result of one or more amino acid deletions in the protein encoded by the TREX1 gene in the cancer cells. In some embodiments of any of the methods described herein, identifying the subject as having cancer cells with decreased level and / or activity of TREX1 comprises detecting one or more amino acid deletions in the protein encoded by the TREX1 gene in the cancer cells. In some embodiments of any of the methods described herein, the decreased level and / or activity of TREX1 is the result of one or more inactivating amino acid substitutions in the protein encoded by the TREX1 gene in the cancer cells. In some embodiments of any of the methods described herein, identifying the subject as having cancer cells with decreased expression and / or activity of TREX1 comprises detecting one or more inactivating amino acid substitutions in the protein encoded by the TREX1 gene in the cancer cells.

[0019] In some embodiments of any of the methods described herein, the increased cGAS / STING signaling pathway activity is a result of a decreased level and / or activity of BRCA1 in the cancer cell. In some embodiments of any of the methods described herein, the decreased level and / or activity of BRCA1 in the cancer cell is a result of a frameshift mutation in the BRCA1 gene. In some embodiments of any of the methods described herein, the frameshift mutation in the BRCA1 gene is an E111Gfs*3 frameshift insertion. In some embodiments of any of the methods described herein, the decreased level and / or activity of BRCA1 in the cancer cell is a result of a BRCA1 gene loss in the cancer cell. In some embodiments of any of the methods described herein, the decreased level and / or activity of BRCA1 in the cancer cell is a result of one or more amino acid deletions in the protein encoded by the BRCA1 gene. In some embodiments of any of the methods described herein, the decreased level and / or activity of BRCA1 in the cancer cell is a result of one or more inactivating amino acid substitutions in the protein encoded by the BRCA1 gene.

[0020] In some embodiments of any of the methods described herein, the increased cGAS / STING signaling pathway activity is a result of a decreased level and / or activity of the BRCA2 gene. In some embodiments of any of the methods described herein, the decreased level and / or activity of BRCA2 in the cancer cell is a result of a frameshift mutation in the BRCA2 gene. In some embodiments of any of the methods described herein, the frameshift mutation in the BRCA2 gene is a N1784Kfs*3 frameshift insertion. In some embodiments of any of the methods described herein, the decreased level and / or activity of BRCA2 in the cancer cell is a result of a BRCA2 gene loss in the cancer cell. In some embodiments of any of the methods described herein, the decreased level and / or activity of BRCA2 in the cancer cell is a result of one or more amino acid deletions in the protein encoded by the BRCA2 gene. In some embodiments of any of the methods described herein, the decreased level and / or activity of BRCA2 in the cancer cell is a result of one or more inactivating amino acid substitutions in the protein encoded by the BRCA2 gene.

[0021] In some embodiments of any of the methods described herein, the increased cGAS / STING signaling pathway activity is a result of a decrease in the level and / or activity of SAMHD1 in the cancer cell. In some embodiments of any of the methods described herein, the decreased level and / or activity of SAMHD1 in the cancer cell is a result of one or more inactivating amino acid substitutions in the protein encoded by the SAMHD1 gene in the cancer cell. In some embodiments of any of the methods described herein, the one or more inactivating amino acid substitutions in the protein encoded by the SAMHD1 gene are V133I amino acid substitutions. In some embodiments of any of the methods described herein, the decreased level and / or activity of SAMHD1 in the cancer cell is a result of SAMHD1 gene loss in the cancer cell. In some embodiments of any of the methods described herein, the decreased level and / or activity of SAMHD1 in the cancer cell is a result of one or more amino acid deletions in the protein encoded by the SAMHD1 gene.

[0022] In some embodiments of any of the methods described herein, the increase in cGAS / STING signaling pathway activity is a result of a decrease in the level and / or activity of DNASE2 in the cancer cell. In some embodiments of any of the methods described herein, the decrease in the level and / or activity of DNASE2 in the cancer cell is a result of one or more inactivating amino acid substitutions in the protein encoded by the DNASE2 gene in the cancer cell. In some embodiments of any of the methods described herein, the one or more inactivating amino acid substitutions in the protein encoded by the DNASE2 gene are R314W amino acid substitutions. In some embodiments of any of the methods described herein, the decrease in the level and / or activity of DNASE2 in the cancer cell is a result of DNASE2 gene loss in the cancer cell. In some embodiments of any of the methods described herein, the decrease in the level and / or activity of DNASE2 in the cancer cell is a result of one or more amino acid deletions in the protein encoded by the DNASE2 gene.

[0023] In some embodiments of any of the methods described herein, the increased cGAS / STING signaling pathway activity is a result of a decreased level and / or activity of BLM in the cancer cell. In some embodiments of any of the methods described herein, the decreased level and / or activity of BLM in the cancer cell is a result of a frameshift mutation in the BLM gene. In some embodiments of any of the methods described herein, the frameshift mutation in the BLM gene is a N515Mfs*16 frameshift deletion. In some embodiments of any of the methods described herein, the decreased level and / or activity of BLM in the cancer cell is a result of a BLM gene loss in the cancer cell. In some embodiments of any of the methods described herein, the decreased level and / or activity of BLM in the cancer cell is a result of one or more amino acid deletions in the protein encoded by the BLM gene. In some embodiments of any of the methods described herein, the decreased level and / or activity of BLM in the cancer cell is a result of one or more inactivating amino acid substitutions in the protein encoded by the BLM gene.

[0024] In some embodiments of any of the methods described herein, the increased cGAS / STING signaling pathway activity is a result of a decreased level and / or activity of PARP1 in the cancer cells. In some embodiments of any of the methods described herein, the decreased level and / or activity of PARP1 in the cancer cells is a result of a frameshift mutation in the PARP1 gene. In some embodiments of any of the methods described herein, the frameshift mutation in the PARP1 gene is a S507Afs*17 frameshift deletion. In some embodiments of any of the methods described herein, the decreased level and / or activity of PARP1 in the cancer cells is a result of PARP1 gene loss in the cancer cells. In some embodiments of any of the methods described herein, the decreased level and / or activity of PARP1 in the cancer cells is a result of one or more amino acid deletions in the protein encoded by the PARP1 gene. In some embodiments of any of the methods described herein, the decreased level and / or activity of PARP1 in the cancer cells is a result of one or more inactivating amino acid substitutions in the protein encoded by the PARP1 gene.

[0025] In some embodiments of any of the methods described herein, the increased cGAS / STING signaling pathway activity is a result of a decreased level and / or activity of RPA1 in the cancer cells. In some embodiments of any of the methods described herein, the decreased level and / or activity of RPA1 in the cancer cells is a result of a mutation that causes aberrant RPA1 mRNA splicing in the cancer cells. In some embodiments of any of the methods described herein, the mutation that causes aberrant RPA1 mRNA splicing in the cancer cells is a X12 splice mutation. In some embodiments of any of the methods described herein, the decreased level and / or activity of RPA1 in the cancer cells is a result of RPA1 gene loss in the cancer cells. In some embodiments of any of the methods described herein, the decreased level and / or activity of RPA1 in the cancer cells is a result of one or more amino acid deletions in the protein encoded by the RPA1 gene. In some embodiments of any of the methods described herein, the decreased level and / or activity of RPA1 in the cancer cells is a result of one or more inactivating amino acid substitutions in the protein encoded by the RPA1 gene.

[0026] In some embodiments of any of the methods described herein, the increased cGAS / STING signaling pathway activity is a result of a decreased level and / or activity of RAD51 in the cancer cell. In some embodiments of any of the methods described herein, the decreased level and / or activity of RAD51 in the cancer cell is a result of one or more inactivating amino acid substitutions in the protein encoded by the RAD51 gene. In some embodiments of any of the methods described herein, the one or more inactivating amino acid substitutions in the protein encoded by the RAD51 gene are R254* amino acid substitutions. In some embodiments of any of the methods described herein, the decreased level and / or activity of RAD51 in the cancer cell is a result of RAD51 gene loss in the cancer cell. In some embodiments of any of the methods described herein, the decreased level and / or activity of RAD51 in the cancer cell is a result of one or more amino acid deletions in the protein encoded by the RAD51 gene.

[0027] In some embodiments of any of the methods described herein, the increased cGAS / STING signaling pathway activity is the result of increased levels and / or activity of MUS81 in the cancer cells. In some embodiments of any of the methods described herein, the increased levels and / or activity of MUS81 in the cancer cells is the result of MUS81 gene amplification in the cancer cells. In some embodiments of any of the methods described herein, the increased levels and / or activity of MUS81 in the cancer cells is the result of one or more activating amino acid substitutions in the protein encoded by the MUS81 gene.

[0028] In some embodiments of any of the methods described herein, the increased cGAS / STING signaling pathway activity is a result of increased levels and / or activity of IFI16 in the cancer cells. In some embodiments of any of the methods described herein, the increased levels and / or activity of IFI16 in the cancer cells is a result of IFI16 gene amplification in the cancer cells. In some embodiments of any of the methods described herein, the increased levels and / or activity of IFI16 in the cancer cells is a result of one or more activating amino acid substitutions in the protein encoded by the IFI16 gene.

[0029] In some embodiments of any of the methods described herein, the increased cGAS / STING signaling pathway activity is the result of increased levels and / or activity of cGAS in the cancer cells. In some embodiments of any of the methods described herein, the increased levels and / or activity of cGAS in the cancer cells is the result of cGAS gene amplification in the cancer cells. In some embodiments of any of the methods described herein, the increased levels and / or activity of cGAS in the cancer cells is the result of one or more activating amino acid substitutions in the protein encoded by the cGAS gene.

[0030] In some embodiments of any of the methods described herein, the increased cGAS / STING signaling pathway activity is the result of increased levels and / or activity of DDX41 in cancer cells. In some embodiments of any of the methods described herein, the increased levels and / or activity of DDX41 in cancer cells is the result of DDX41 gene amplification in cancer cells. In some embodiments of any of the methods described herein, the increased levels and / or activity of DDX41 in cancer cells is the result of one or more activating amino acid substitutions in the protein encoded by the DDX41 gene.

[0031] In some embodiments of any of the methods described herein, the increased cGAS / STING signaling pathway activity is the result of increased levels and / or activity of EXO1 in the cancer cell. In some embodiments of any of the methods described herein, the increased levels and / or activity of EXO1 in the cancer cell is the result of EXO1 gene amplification in the cancer cell. In some embodiments of any of the methods described herein, the increased levels and / or activity of EXO1 in the cancer cell is the result of one or more activating amino acid substitutions in the protein encoded by the EXO1 gene.

[0032] In some embodiments of any of the methods described herein, the increased cGAS / STING signaling pathway activity is the result of increased levels and / or activity of DNA2 in the cancer cells. In some embodiments of any of the methods described herein, the increased levels and / or activity of DNA2 in the cancer cells is the result of DNA2 gene amplification in the cancer cells. In some embodiments of any of the methods described herein, the increased levels and / or activity of DNA2 in the cancer cells is the result of one or more activating amino acid substitutions in the protein encoded by the DNA2 gene.

[0033] In some embodiments of any of the methods described herein, the increased cGAS / STING signaling pathway activity is a result of increased levels and / or activity of RBBP8 (CtIP) in cancer cells. In some embodiments of any of the methods described herein, the increased levels and / or activity of RBBP8 (CtIP) in cancer cells is a result of RBBP8 (CtIP) gene amplification in cancer cells. In some embodiments of any of the methods described herein, the increased levels and / or activity of RBBP8 (CtIP) in cancer cells is a result of one or more activating amino acid substitutions in the protein encoded by the RBBP8 (CtIP) gene.

[0034] In some embodiments of any of the methods described herein, the increased cGAS / STING signaling pathway activity is the result of increased levels and / or activity of MRE11 in the cancer cell. In some embodiments of any of the methods described herein, the increased levels and / or activity of MRE11 in the cancer cell is the result of MRE11 gene amplification in the cancer cell. In some embodiments of any of the methods described herein, the increased levels and / or activity of MRE11 in the cancer cell is the result of one or more activating amino acid substitutions in the protein encoded by the MRE11 gene.

[0035] Some embodiments of any of the methods described herein further include administering a selected treatment to the subject. Some embodiments of any of the methods described herein further include administering a therapeutically effective amount of a STING antagonist to a subject identified as having an increased likelihood of responding to treatment with a STING antagonist.

[0036] In some embodiments of any of the methods described herein, the subject has been diagnosed or identified as having cancer. In some embodiments of any of the methods described herein, the cancer is selected from the group consisting of renal clear cell carcinoma, papillary renal cell carcinoma, chromophobe renal cell carcinoma, uveal melanoma, tongue squamous cell carcinoma, breast cancer, osteosarcoma, and skin cancer. In some embodiments of any of the methods described herein, the cancer is selected from the group consisting of renal clear cell carcinoma, uveal melanoma, tongue squamous cell carcinoma, breast cancer, and skin cancer.

[0037] The term "STING antagonist" as used herein refers to an agent that decreases one or both of the following: (i) the activity of STING (e.g., any exemplary activity of STING described herein) (e.g., compared to the level of STING activity in the absence of the agent) and (ii) the expression level of STING in a mammalian cell (e.g., using any exemplary detection method described herein) (e.g., compared to the expression level of STING in a mammalian cell not contacted with the agent). Non-limiting examples of STING antagonists are described herein.

[0038] The term "STING" as used herein is intended to include, but is not limited to, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide strands, complementary sequences, peptides, polypeptides, proteins, homologous and / or orthologous STING molecules, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, different species, and active fragments thereof.

[0039] The term "cGAS" as used herein is intended to include, but is not limited to, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide strands, complementary sequences, peptides, polypeptides, proteins, homologous and / or orthologous cGAS molecules, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, different species, and active fragments thereof.

[0040] As used herein, the term "acceptable" in reference to a formulation, composition, or ingredient means that there are no lasting adverse effects on the general health of the subject being treated.

[0041] "API" means active pharmaceutical ingredient.

[0042] The term "effective amount" or "therapeutically effective amount" as used herein refers to an amount of STING antagonist administered that is sufficient to alleviate to some extent one or more symptoms of the disease or condition being treated. The result includes a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired change in a biological system. For example, an "effective amount" in therapeutic applications refers to the amount of a composition comprising a STING antagonist disclosed herein that is required to achieve a clinically significant reduction in disease symptoms. The appropriate "effective" amount in any individual case can be determined using any suitable technique, such as a dose escalation study.

[0043] The term "excipient" or "pharmaceutically acceptable excipient" means a pharma- ceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one aspect, each component is "pharmaceutically acceptable" in the sense of being compatible with the other components of a pharmaceutical formulation, suitable for use in contact with the tissues or organs of humans and animals, without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. For example, Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0044] The term "pharmaceutically acceptable salt" may refer to a pharmaceutically acceptable addition salt prepared from a pharmaceutically acceptable non-toxic acid, including inorganic and organic acids. In certain cases, a pharmaceutically acceptable salt is obtained by reacting a compound described herein with an acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. The term "pharmaceutically acceptable salt" may also refer to a pharmaceutically acceptable addition salt prepared by reacting a compound having an acidic group with a base to form a salt, such as an alkali metal salt, such as an ammonium salt, a sodium salt, or a potassium salt, an alkaline earth metal salt, such as a calcium salt or a magnesium salt, a salt of an organic base, such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and a salt with an amino acid, such as arginine, lysine, etc., or by other methods already established. There is no particular limit to the pharmacologically acceptable salt, so long as it can be used in medicine. Examples of salts that the compounds described herein form with bases include their salts with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; their salts with organic bases such as methylamine, ethylamine, and ethanolamine; their salts with basic amino acids such as lysine and ornithine; and ammonium salts. The salts may be acid addition salts, exemplified by acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.

[0045] The term "pharmaceutical composition" refers to a mixture of a STING antagonist as described herein with other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, and / or thickening agents (collectively referred to herein as "excipients"). The pharmaceutical composition facilitates administration of the STING antagonist to an organism. Multiple techniques of administering a compound exist in the art, including, but not limited to, rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0046] The term "subject" refers to an animal, including, but not limited to, a primate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. As used herein, the terms "subject" and "patient" are used interchangeably with respect to a mammalian subject, such as a human. In some embodiments of any of the methods described herein, the subject is 1 year or older, 2 years or older, 4 years or older, 5 years or older, 10 years or older, 12 years or older, 13 years or older, 15 years or older, 16 years or older, 18 years or older, 20 years or older, 25 years or older, 30 years or older, 35 years or older, 40 years or older, 45 years or older, 50 years or older, 55 years or older, 60 years or older, 65 years or older, 70 years or older, 75 years or older, 80 years or older, 85 years or older, 90 years or older, 95 years or older, 100 years or older, or 105 years or older.

[0047] In some embodiments of any of the methods described herein, the subject has already been diagnosed or identified as having a disease associated with STING activity (e.g., cancer, e.g., any of the exemplary types of cancer described herein). In some embodiments of any of the methods described herein, the subject is suspected of having cancer (e.g., any of the exemplary cancers described herein). In some embodiments of any of the methods described herein, the subject exhibits one or more (e.g., two, three, four, or five) symptoms of cancer (e.g., any of the exemplary cancers described herein).

[0048] In some embodiments of any of the methods described herein, the subject is a participant in a clinical trial. In some embodiments of any of the methods described herein, the subject has previously been administered a pharmaceutical composition, and it has been determined that the different pharmaceutical composition is not therapeutically effective.

[0049] The term "administration" or "administering" refers to a method of administering a pharmaceutical composition or compound to an invertebrate or vertebrate, including fish, birds, and mammals (e.g., humans). In some aspects, administration is performed, for example, orally, intravenously, subcutaneously, intranasally, transdermally, intraperitoneally, intramuscularly, intrapulmonary, intralymphatic, topically, intraocularly, intravaginally, rectally, intrathecally, or intracystiically. The method of administration may depend on various factors, such as the site of disease, the severity of disease, and the components of the pharmaceutical composition.

[0050] The terms "treat," "treating," and "treatment" in the context of treating a disease or disorder are intended to include alleviating or arresting the disorder, disease, or condition, or one or more symptoms associated with the disorder, disease, or condition; or slowing the progression, metastasis, or worsening of the disease, disorder, or condition, or one or more symptoms thereof.

[0051] The phrase "elevated levels" or "increased levels" as used herein can be, for example, an increase of 1.1-fold to 100-fold or more (e.g., up to 200-fold) as compared to a reference level (e.g., any of the exemplary reference levels described herein). In some aspects, "elevated levels" or "increased levels" refers to an increase of at least 1% (e.g., at least 2%, at least 4, at least 6%, at least 8%, at least 10%, at least 12%, at least 14%, at least 16%, at least 18%, at least 20%, at least 22%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 90%, at least 10 ... The increase may be 5%, at least 99%, at least 100%, at least 110%, at least 120%, at least 130%, at least 140%, at least 150%, at least 160%, at least 170%, at least 180%, at least 190%, at least 200%, at least 220%, at least 250%, at least 280%, at least 300%, at least 320%, at least 350%, at least 380%, at least 400%, at least 420%, at least 450%, at least 480%, at least 500%, at least 600%, at least 700%, at least 800%, at least 900%, or at least 1000%).

[0052] As used herein, the phrase "a decrease in the level" can be, for example, a decrease of at least 1% (e.g., at least 2%, at least 4, at least 6%, at least 8%, at least 10%, at least 12%, at least 14%, at least 16%, at least 18%, at least 20%, at least 22%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) as compared to a reference level (e.g., any of the exemplary reference levels described herein).

[0053] The phrase "reduced levels of TREX1" refers to a reduction in the levels of TREX1 protein and / or TREX1 mRNA in mammalian cells. For example, a reduction in the levels of TREX1 can be the result of a TREX1 gene loss (in one or both alleles), a mutation in the regulatory region of the TREX1 gene that results in reduced transcription of the TREX1 gene, or a mutation that results in the production of a TREX1 protein that exhibits reduced stability and / or half-life in mammalian cells.

[0054] The phrase "protein activity" (or "activity" of a particular protein) refers to one or more activities of a protein (e.g., enzymatic activity, localization activity, binding activity (e.g., binding to another protein or binding to a non-protein, e.g., nucleic acid). For example, a decrease in activity of a protein in a mammalian cell can be the result of an amino acid deletion in the protein or an amino acid substitution in the protein, e.g., as compared to the wild-type protein. In some cases, an increase in activity of a protein in a mammalian cell can be the result of, e.g., gene amplification, or the result of an activating amino acid substitution in the protein, e.g., as compared to the wild-type protein.

[0055] The phrase "TREX1 activity" refers to 3'-exonuclease activity. For example, a decrease in TREX1 activity in a mammalian cell may be the result of, for example, a TREX1 gene loss (e.g., in one or both alleles), a substitution, deletion, and / or insertion of one or more nucleotides in the TREX1 gene, a deletion, substitution, insertion, truncation, or other modification of one or more amino acids to the protein sequence of the TREX1 protein, or one or more post-translational modifications to the TREX1 protein that change the activity, localization, or function of the TREX1 protein.

[0056] The term "increased STING pathway activity" refers to an increase in the direct activity of STING in a mammalian cell (e.g., translocation of STING from the endoplasmic reticulum to the perinuclear region, or activation of TBK1 (TANK-binding kinase 1)); or an increase in upstream activity or mutations in a mammalian cell (e.g., any of the exemplary mutations or single nucleotide polymorphisms described herein) that result in increased STING pathway activity in a mammalian cell (e.g., a decrease in the level or activity of one or more of BRCA1, BRCA2, SAMHD1, DNASE2, BLM, PARP1, RPA1, and RAD51 (e.g., compared to any of the exemplary reference levels described herein), or an increase in the level or activity of one or more of MUS81, IFI16, cGAS, DDX41, EXO1, DNA2, RBBP8, and MRE11 (e.g., compared to any of the exemplary reference levels described herein)).

[0057] The decrease in the level or activity of one or more of BRCA1, BRCA2, SAMHD1, DNASE2, BLM, PARP1, RPA1, and RAD51 (e.g., in cancer cells) can be caused by any mechanism.

[0058] In some embodiments, the decreased level or activity of BRCA1 can be the result of a frameshift mutation in the BRCA1 gene (e.g., an E111Gfs*3 frameshift insertion). In some embodiments, the decreased level or activity of BRCA1 can be the result of BRCA1 gene loss (e.g., loss of one allele of BRCA1 or loss of both alleles of BRCA1). In some embodiments, the decreased level or activity of BRCA1 can be the result of one or more amino acid deletions in the protein encoded by the BRCA1 gene. In some embodiments, the decreased level or activity of BRCA1 can be the result of one or more inactivating amino acid substitutions in the protein encoded by the BRCA1 gene.

[0059] In some embodiments, the decreased level or activity of the BRCA2 gene may be the result of a frameshift mutation in the BRCA2 gene (e.g., a N1784Kfs*3 frameshift insertion). In some embodiments, the decreased level or activity of BRCA2 may be the result of BRCA2 gene loss (e.g., loss of one allele of BRCA2 or loss of both alleles of BRCA2). In some embodiments, the decreased level or activity of BRCA2 may be the result of one or more amino acid deletions in the protein encoded by the BRCA2 gene. In some embodiments, the decreased level or activity of BRCA2 may be the result of one or more inactivating amino acid substitutions in the protein encoded by the BRCA2 gene.

[0060] In some embodiments, the decreased level or activity of SAMHD1 can be the result of one or more inactivating amino acid substitutions (e.g., a V133I amino acid substitution) in the protein encoded by the SAMHD1 gene. In some embodiments, the decreased level or activity of SAMHD1 can be the result of gene loss (e.g., loss of one allele of SAMHD1 or loss of both alleles of SAMHD1). In some embodiments, the decreased level or activity of SAMHD1 can be the result of one or more amino acid deletions in the protein encoded by the SAMHD1 gene.

[0061] In some embodiments, the decrease in DNASE2 level or activity can be the result of one or more inactivating mutations (e.g., R314W amino acid substitution) in the protein encoded by the DNASE2 gene. In some embodiments, the decrease in DNASE2 level or activity can be the result of DNASE2 gene loss (e.g., loss of one allele of DNASE2 or loss of both alleles of DNASE2). In some embodiments, the decrease in DNASE2 level or activity can be the result of one or more amino acid deletions in the protein encoded by the DNASE2 gene.

[0062] In some embodiments, the decreased level or activity of BLM can be the result of a frameshift mutation in the BLM gene (e.g., a N515Mfs*16 frameshift deletion). In some embodiments, the decreased level or activity of BLM can be the result of a BLM gene loss (e.g., loss of one allele of BLM or loss of both alleles of BLM). In some embodiments, the decreased level or activity of BLM can be the result of one or more amino acid deletions in the protein encoded by the BLM gene. In some embodiments, the decreased level or activity of BLM can be the result of one or more inactivating amino acid substitutions in the protein encoded by the BLM gene.

[0063] In some embodiments, the decrease in PARP1 level or activity can be the result of a frameshift mutation in the PARP1 gene (e.g., S507Afs*17 frameshift deletion). In some embodiments, the decrease in PARP1 level or activity can be the result of gene loss (e.g., loss of one allele of PARP1 or loss of both alleles of PARP1). In some embodiments, the decrease in PARP1 level or activity can be the result of one or more amino acid deletions in the protein encoded by the PARP1 gene. In some embodiments, the decrease in PARP1 level or activity can be the result of one or more inactivating amino acid substitutions in the protein encoded by the PARP1 gene.

[0064] In some embodiments, the reduction in RPA1 level or activity can be the result of a mutation (e.g., X12 splice mutation) that causes abnormal RPA mRNA splicing. In some embodiments, the reduction in RPA1 level or activity can be the result of RPA1 gene loss (e.g., loss of one allele of RPA1 or loss of both alleles of RPA1). In some embodiments, the reduction in RPA1 level or activity can be the result of one or more amino acid deletions in the protein encoded by the RPA1 gene. In some embodiments, the reduction in RPA1 level or activity can be the result of one or more inactivating amino acid substitutions in the protein encoded by the RPA1 gene.

[0065] In some embodiments, the decreased level or activity of RAD51 can be the result of one or more inactivating mutations (e.g., R254* mutations) in the protein encoded by the RAD51 gene. In some embodiments, the decreased level or activity of RAD51 can be the result of RAD51 gene loss (e.g., loss of one allele of RAD51 or loss of both alleles of RAD51). In some embodiments, the decreased level or activity of RAD51 can be the result of one or more amino acid deletions in the protein encoded by the RAD51 gene.

[0066] Increased levels or activity of one or more of MUS81, IFI16, cGAS, DDX41, EXO1, DNA2, RBBP8, or MRE11 (e.g., in cancer cells) can be caused by any mechanism.

[0067] In some embodiments, the increased level or activity of MUS81 can be the result of MUS81 gene amplification. In some embodiments, the increased level or activity of MUS81 can be the result of one or more activating amino acid substitutions in the protein encoded by the MUS81 gene.

[0068] In some embodiments, the increased level or activity of IFI16 may be the result of IFI16 gene amplification. In some embodiments, the increased level or activity of IFI16 may be the result of one or more activating amino acid substitutions in the protein encoded by the IFI16 gene.

[0069] In some embodiments, the increased level or activity of cGAS can be the result of cGAS gene amplification, hi some embodiments, the increased level or activity of cGAS can be the result of one or more activating amino acid substitutions in the protein encoded by the cGAS gene.

[0070] In some embodiments, the increased level or activity of DDX41 can be the result of DDX41 gene amplification. In some embodiments, the increased level or activity of DDX41 can be the result of one or more activating amino acid substitutions in the protein encoded by the DDX41 gene.

[0071] In some embodiments, the increased level or activity of EXO1 can be the result of EXO1 gene amplification. In some embodiments, the increased level or activity of EXO1 can be the result of one or more activating amino acid substitutions in the protein encoded by the EXO1 gene.

[0072] In some embodiments, the increased level or activity of DNA2 can be the result of DNA2 gene amplification. In some embodiments, the increased level or activity of DNA2 can be the result of one or more activating amino acid substitutions in the protein encoded by the DNA2 gene.

[0073] In some embodiments, the increased level or activity of RBBP8 (also called CtIP) may be the result of RBBP8 gene amplification. In some embodiments, the increased level or activity of RBBP8 may be the result of one or more activating amino acid substitutions in the protein encoded by the RBBP8 gene.

[0074] In some embodiments, the increased level or activity of MRE11 can be the result of MRE11 gene amplification. In some embodiments, the increased level or activity of MRE11 can be the result of one or more activating amino acid substitutions in the protein encoded by the MRE11 gene.

[0075] Non-limiting examples of human protein and cDNA sequences for STING, TREX1, BRCA1, BRCA2, SAMHD1, DNASE2, BLM, PARP1, RPA1, RAD51, MUS81, IFI16, cGAS, DDX41, EXO1, DNA2, RBBP8 (CtIP), and MRE11 are shown below (SEQ ID NOs: 1-89). It will be understood that other natural variants of these sequences may exist, and that the name of the gene may be used to refer to the gene or its protein product. TIFF2024502755000001.tif36153TIFF2024502755000002.tif218153TIFF2024502755000003.tif213153

[0076] Some embodiments of any of the methods described herein include determining the expression level of mRNA or protein encoded by one or more of STING, TREX1, BRCA1, BRCA2, SAMHD1, DNASE2, BLM, PARP1, RPA1, RAD51, MUS81, IFI16, cGAS, DDX41, EXO1, DNA2, RBBP8 (CtIP), and MRE11. In some examples of any of the methods described herein, determining increased STING or cGAS signaling activity may include, for example, detecting a decrease in the level of mRNA or protein encoded by one or more of BRCA1, BRCA2, SAMHD1, DNASE2, BLM, PARP1, RPA1, and RAD51 in the mammalian cell (e.g., compared to any of the exemplary reference levels described herein), and / or detecting an increase in the level of mRNA or protein encoded by one or more of STING, MUS81, IFI16, cGAS, DDX41, EXO1, DNA2, RBBP8 (CtIP), and MRE11.

[0077] In some embodiments of any of the methods described herein, the increased cGAS / STING signaling activity is characterized by a gain-of-function mutation (e.g., gene amplification of one or more of MUS81, IFI16, cGAS, DDX41, EXO1, DNA2, RBBP8 (CtIP), and MRE1, or one or more activating amino acid substitutions in the proteins encoded by the genes); gene deletion of one or more of BRCA1, BRCA2, SAMHD1, DNASE2, BLM, PARP1, RPA1, and RAD51; one or more amino acid deletions in the proteins encoded by one or more of BRCA1, BRCA2, SAMHD1, DNASE2, BLM, PARP1, RPA1, and RAD51; one or more inactivating amino acid mutations in the proteins encoded by one or more of BRCA1, BRCA2, SAMHD1, DNASE2, BLM, PARP1, RPA1, or RAD51; Alternatively, it can be confirmed by detection of a frameshift mutation in one or more of BRCA1, BRCA2, SAMHD1, DNASE2, BLM, PARP1, RPA1, and RAD51.

[0078] Some embodiments of any of the methods described herein may include determining the expression level of mRNA or protein encoded by TREX1. In some embodiments, a decrease in the level and / or activity of TREX1 can be determined by detecting a loss-of-function TREX1 mutation, a TREX1 gene deletion, one or more amino acid deletions in the protein encoded by TREX1, and one or more amino acid substitutions in the protein encoded by the TREX1 gene.

[0079] Methods for detecting the level of each of these exemplary cGAS / STING signaling pathway activities are described herein. Further examples of cGAS / STING signaling pathway activities, and methods for detecting the levels thereof, are known in the art.

[0080] As used herein, a "gain-of-function mutation" refers to a substitution, deletion, and / or insertion of one or more nucleotides in a gene that results in the production of a protein encoded by the gene that exhibits increased activity or activities in a mammalian cell compared to the version of the protein encoded by the corresponding wild-type gene. In some embodiments, the gain-of-function mutation may be a gene amplification of one or more of MUS81, IFI16, cGAS, DDX41, EXO1, DNA2, RBBP8 (CtIP), STING, and MRE1, or one or more activating amino acid substitutions in the protein encoded by the gene.

[0081] As used herein, a "loss-of-function mutation" refers to a substitution, deletion, and / or insertion of one or more nucleotides in a gene that results in a decrease in the expression level of the encoded protein compared to the expression level by the corresponding wild-type gene and / or results in the expression of the protein encoded by the gene exhibiting a decrease in one or more activities in a mammalian cell compared to the version of the protein encoded by the corresponding wild-type gene. In some embodiments, a loss-of-function mutation can be a gene deletion, a deletion of one or more amino acids in the protein encoded by the gene, or a substitution of one or more inactivating amino acids in the protein encoded by the gene.

[0082] The terms "hydrogen" and "H" are used interchangeably herein.

[0083] The term "halo" means fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

[0084] The term "alkyl" refers to a hydrocarbon chain, which may be a straight or branched chain, containing the indicated number of carbon atoms. For example, C 1~10indicates that the group may have 1 to 10 (inclusive) carbon atoms in it. Non-limiting examples include methyl, ethyl, isopropyl, tert-butyl, and n-hexyl.

[0085] The term "haloalkyl" means an alkyl in which one or more hydrogen atoms are replaced with an independently selected halo.

[0086] The term "alkoxy" means an -O-alkyl group (eg, -OCH3).

[0087] The term "carbocycle" as used herein includes optionally substituted aromatic or non-aromatic cyclic hydrocarbon groups having 3 to 10 carbons, such as 3 to 8 carbons, for example 3 to 7 carbons. Examples of carbocycles include 5-, 6-, and 7-membered carbocycles.

[0088] The term "heterocycle" refers to an aromatic or non-aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms in the case of a monocyclic, 1-6 heteroatoms in the case of a bicyclic, or 1-9 heteroatoms in the case of a tricyclic, the heteroatoms being selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 N, O, or S heteroatoms in the case of a monocyclic, bicyclic, or tricyclic system, respectively), in which 0, 1, 2, or 3 atoms of each ring may be substituted by a substituent. Examples of heterocycles include 5-, 6-, and 7-membered heterocycles.

[0089] The term "cycloalkyl" as used herein includes optionally substituted aromatic or non-aromatic cyclic hydrocarbon groups having 3 to 10 carbons, e.g., 3 to 8 carbons, e.g., 3 to 7 carbons. Examples of cycloalkyl include 5-, 6-, and 7-membered rings. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

[0090] The term "heterocycloalkyl" refers to an aromatic or non-aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms in the case of a monocyclic, 1-6 heteroatoms in the case of a bicyclic, or 1-9 heteroatoms in the case of a tricyclic, the heteroatoms being selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 N, O, or S heteroatoms in the case of a monocyclic, bicyclic, or tricyclic system, respectively), and 0, 1, 2, or 3 atoms of each ring may be substituted with a substituent. Examples of heterocycloalkyl include 5-, 6-, and 7-membered heterocycles. Examples include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like.

[0091] The term "hydroxy" refers to an OH group.

[0092] The term "amino" refers to the group NH2.

[0093] The term "oxo" means O. For example, replacement of a CH group with oxo gives a C=O group.

[0094] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this disclosure belongs.All patents, applications, published applications, and other publications are incorporated by reference in their entirety.In the event that there are multiple definitions for terms in this specification, the definitions in this section shall prevail unless otherwise stated.

[0095] Other features and advantages of the invention will be apparent from the following detailed description and drawings, and from the claims. [Brief description of the drawings]

[0096] [Figure 1]1 is a graph showing the correlation between allele number of the TREX1 gene and type 1 interferon-inducible gene set expression in human subjects with renal cell carcinoma. [Diagram 2] 1 is a graph showing survival probability over time in subjects with renal cell carcinoma and with diploid or amplified TREX1 or deleted TREX1. [Diagram 3] 1 is a graph of overall survival over time in papillary renal cell carcinoma subjects with or without deleted TREX1. [Figure 4A] Figures 4A and 4B are graphs showing the correlation between TREX1 allele copy number (TREX1 deletion or TREX1 amplification) and STING-dependent interferon-1 activity gene signature expression in subjects with renal cell carcinoma. [Figure 4B] See legend to Figure 4A. [Diagram 5] 1 is a graph showing percent subject survival over time in subjects with uveal melanoma and with diploid or hypodiploid TREX1. [Figure 6] 1 is a graph showing percent subject survival over time in subjects with osteosarcoma and with high or low TREX protein expression. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0097] Detailed Description The present invention is based on the discovery that cancer cells having decreased levels and / or activity of TREX1 and / or increased cGAS / STING signaling pathway activity are more sensitive to treatment with a STING antagonist. In light of these discoveries, provided herein are methods of treating a subject in need thereof with a treatment comprising a STING antagonist, methods of selecting a treatment comprising a STING antagonist for a subject in need thereof, methods of selecting a subject for treatment with a STING antagonist, methods of selecting a subject for participation in a clinical trial with a STING antagonist, and methods of predicting a subject's responsiveness to a STING antagonist (e.g., a compound of any one of Formulas I-XXIV (e.g., Formulas XI-XV) or Formulas M1-M6 (e.g., Formulas M3-M6), or a compound set forth in Table C1).

[0098] Non-limiting aspects of these methods are described below and can be used in any combination without limitation. Additional aspects of these methods are known in the art.

[0099] Treatment Provided herein are methods of treating a subject in need thereof (e.g., any of the exemplary subjects described herein), comprising: (a) identifying a subject having cells (e.g., cancer cells) with (i) a decrease in the level and / or activity of TREX1 (e.g., a decrease of 1% to about 99%, or any subrange of this range as described herein) (e.g., compared to a reference level), and / or (ii) an increase in cGAS / STING signaling pathway activity (e.g., an increase of 1% to 1000%, or any subrange of this range as described herein) (e.g., compared to a reference level); and (b) administering to the identified subject a treatment comprising a therapeutically effective amount of a STING antagonist, or a pharma- ceutical acceptable salt, solvate, or co-crystal thereof, wherein the STING antagonist is a compound of any one of Formulas I-XXIV (e.g., Formulas XI-XV) or Formulas M1-M6 (e.g., Formulas M3-M6), or a compound set forth in Table C1.

[0100] A method of treating a subject in need thereof (e.g., any of the exemplary subjects described herein), comprising: (I) a subject identified as having cells (e.g., cancer cells) having one or both of: (i) a decrease in the level and / or activity of TREX1 (e.g., a decrease of about 1% to about 99%, or any subrange of this range described herein) (e.g., compared to a reference level); and (ii) an increase in cGAS / STING signaling pathway activity (e.g., an increase of 1% to 1000%, or any subrange of this range described herein) (e.g., compared to a reference level); or (II). Also provided herein are methods comprising administering to a subject identified as having an elevated level of cGAMP in serum or tumor (e.g., an increase of 1% to 1000%, or any subrange of this range described herein) (e.g., compared to a reference level), a treatment comprising a therapeutically effective amount of a STING antagonist, or a pharma- ceutically acceptable salt, solvate, or cocrystal thereof, wherein the STING antagonist is a compound of any one of Formulas I-XXIV (e.g., Formulas XI-XV) or Formulas M1-M6 (e.g., Formulas M3-M6), or a compound set forth in Table C1.

[0101] In some embodiments, the subject is identified as having cancer cells with a decreased level and / or activity of TREX1. In some embodiments, the subject is identified as having an elevated level of cGAMP in a serum sample or tumor sample from the subject. In some embodiments, the subject is identified as having cancer cells with an increased cGAS / STING signaling pathway activity (e.g., an increase of 1% to 1000%, or any subrange of this range described herein) (e.g., compared to a reference level), or the subject is identified as having an elevated level of cGAMP in serum or tumor (e.g., an increase of 1% to 1000%, or any subrange of this range described herein) (e.g., compared to a reference level). In some embodiments, the subject is identified as having cancer cells with both (i) a decreased level and / or activity of TREX1 and (ii) an increased cGAS / STING signaling pathway activity (e.g., an increase of 1% to 1000%, or any subrange of this range described herein) (e.g., compared to a reference level), or the subject is identified as having an elevated level of cGAMP (e.g., an increase of 1% to 1000%, or any subrange of this range described herein) (e.g., compared to a reference level) in serum or tumor. In some embodiments, the subject is identified as having cancer cells with a decreased level of TREX1. In some embodiments, the level of TREX1 is a level of TREX1 protein in the cancer cells. In some embodiments, identifying the subject as having cancer cells with a decreased level of TREX1 comprises detecting a decreased level of TREX1 protein in the cancer cells. In some embodiments, the level of TREX1 is a level of TREX1 mRNA in the cancer cells. In some embodiments, identifying the subject as having cancer cells with a decreased level of TREX1 comprises detecting a decreased level of TREX1 mRNA in the cancer cells.

[0102] In some embodiments, the reduced level and / or activity of TREX1 is a result of TREX1 gene loss in the cancer cells. In some embodiments, the TREX1 gene loss is a loss of one allele of the TREX1 gene. In some embodiments, the TREX1 gene loss is a loss of both alleles of the TREX1 gene. In some embodiments, identifying the subject as having cancer cells with reduced level and / or activity of TREX1 comprises detecting TREX1 gene loss in the cancer cells. In some embodiments, the reduced level and / or activity of TREX1 is a result of one or more amino acid deletions or post-translational modifications of the protein encoded by the TREX1 gene in the cancer cells. In some embodiments, identifying the subject as having cancer cells with reduced level and / or activity of TREX1 comprises detecting one or more amino acid deletions in the protein encoded by the TREX1 gene in the cancer cells. In some embodiments, the reduced level and / or activity of TREX1 is a result of one or more inactivating amino acid substitutions in the protein encoded by the TREX1 gene in the cancer cells. In some embodiments, identifying a subject as having cancer cells with reduced expression and / or activity of TREX1 comprises detecting one or more inactivating amino acid substitutions or post-translational modifications in a protein encoded by the TREX1 gene in the cancer cells.

[0103] In some embodiments, the increased cGAS / STING signaling pathway activity is a result of a decreased level and / or activity of BRCA1 in the cancer cell. In some embodiments, the decreased level and / or activity of BRCA1 in the cancer cell is a result of a frameshift mutation in the BRCA1 gene. In some embodiments, the frameshift mutation in the BRCA1 gene is an E111Gfs*3 frameshift insertion (e.g., a mutation in the BRCA1 gene causing an E111Gfs*3 frameshift insertion relative to SEQ ID NO: 15). In some embodiments, the decreased level and / or activity of BRCA1 in the cancer cell is a result of a BRCA1 gene loss in the cancer cell. In some embodiments, the decreased level and / or activity of BRCA1 in the cancer cell is a result of one or more amino acid deletions in the protein encoded by the BRCA1 gene. In some embodiments, the decreased level and / or activity of BRCA1 in the cancer cell is a result of one or more inactivating amino acid substitutions in the protein encoded by the BRCA1 gene.

[0104] In some embodiments, the increased cGAS / STING signaling pathway activity is a result of a decreased level and / or activity of the BRCA2 gene. In some embodiments, the decreased level and / or activity of BRCA2 in the cancer cell is a result of a frameshift mutation in the BRCA2 gene. In some embodiments, the frameshift mutation in the BRCA2 gene is a N1784Kfs*3 frameshift insertion (e.g., a mutation in the BRCA2 gene causing a N1784Kfs*3 frameshift insertion relative to SEQ ID NO: 25). In some embodiments, the decreased level and / or activity of BRCA2 in the cancer cell is a result of a BRCA2 gene loss in the cancer cell. In some embodiments, the decreased level and / or activity of BRCA2 in the cancer cell is a result of one or more amino acid deletions in the protein encoded by the BRCA2 gene. In some embodiments, the decreased level and / or activity of BRCA2 in the cancer cell is a result of one or more inactivating amino acid substitutions in the protein encoded by the BRCA2 gene.

[0105] In some embodiments, the increase in cGAS / STING signaling pathway activity is the result of a decrease in the level and / or activity of SAMHD1 in cancer cells. In some embodiments, the decrease in the level and / or activity of SAMHD1 in cancer cells is the result of one or more inactivating amino acid substitutions in the protein encoded by the SAMHD1 gene in cancer cells. In some embodiments, the one or more inactivating amino acid substitutions in the protein encoded by the SAMHD1 gene are V133I amino acid substitutions (e.g., a mutation in the SAMHD1 gene that causes a V133I amino acid substitution to SEQ ID NO: 27). In some embodiments, the decrease in the level and / or activity of SAMHD1 in cancer cells is the result of SAMHD1 gene loss in cancer cells. In some embodiments, the decrease in the level and / or activity of SAMHD1 in cancer cells is the result of one or more amino acid deletions in the protein encoded by the SAMHD1 gene.

[0106] In some embodiments, the increase in cGAS / STING signaling pathway activity is the result of a decrease in the level and / or activity of DNASE2 in cancer cells. In some embodiments, the decrease in the level and / or activity of DNASE2 in cancer cells is the result of one or more inactivating amino acid substitutions in the protein encoded by the DNASE2 gene in cancer cells. In some embodiments, the one or more inactivating amino acid substitutions in the protein encoded by the DNASE2 gene are R314W amino acid substitutions (e.g., a mutation in the DNASE2 gene that causes an R314W amino acid substitution to SEQ ID NO: 33). In some embodiments, the decrease in the level and / or activity of DNASE2 in cancer cells is the result of DNASE2 gene loss in cancer cells. In some embodiments, the decrease in the level and / or activity of DNASE2 in cancer cells is the result of one or more amino acid deletions in the protein encoded by the DNASE2 gene.

[0107] In some embodiments, the increased cGAS / STING signaling pathway activity is the result of a decreased level and / or activity of BLM in cancer cells. In some embodiments, the decreased level and / or activity of BLM in cancer cells is the result of a frameshift mutation in the BLM gene. In some embodiments, the frameshift mutation in the BLM gene is a N515Mfs*16 frameshift deletion (e.g., a mutation in the BLM gene causing a N515Mfs*16 frameshift deletion relative to SEQ ID NO: 37). In some embodiments, the decreased level and / or activity of BLM in cancer cells is the result of a BLM gene loss in cancer cells. In some embodiments, the decreased level and / or activity of BLM in cancer cells is the result of one or more amino acid deletions in the protein encoded by the BLM gene. In some embodiments, the decreased level and / or activity of BLM in cancer cells is the result of one or more inactivating amino acid substitutions in the protein encoded by the BLM gene.

[0108] In some embodiments, the increase in cGAS / STING signaling pathway activity is a result of a decrease in the level and / or activity of PARP1 in cancer cells. In some embodiments, the decrease in the level and / or activity of PARP1 in cancer cells is a result of a frameshift mutation in the PARP1 gene. In some embodiments, the frameshift mutation in the PARP1 gene is a S507Afs*17 frameshift deletion (e.g., a mutation in the PARP1 gene causing a S507Afs*17 frameshift deletion relative to SEQ ID NO: 43). In some embodiments, the decrease in the level and / or activity of PARP1 in cancer cells is a result of PARP1 gene loss in cancer cells. In some embodiments, the decrease in the level and / or activity of PARP1 in cancer cells is a result of one or more amino acid deletions in the protein encoded by the PARP1 gene. In some embodiments, the decrease in the level and / or activity of PARP1 in cancer cells is a result of one or more inactivating amino acid substitutions in the protein encoded by the PARP1 gene.

[0109] In some embodiments, the increase in cGAS / STING signaling pathway activity is the result of a decrease in the level and / or activity of RPA1 in cancer cells. In some embodiments, the decrease in the level and / or activity of RPA1 in cancer cells is the result of a mutation that causes aberrant RPA1 mRNA splicing in cancer cells. In some embodiments, the mutation that causes aberrant RPA1 mRNA splicing in cancer cells is a X12 splice mutation. In some embodiments, the decrease in the level and / or activity of RPA1 in cancer cells is the result of RPA1 gene loss in cancer cells. In some embodiments, the decrease in the level and / or activity of RPA1 in cancer cells is the result of one or more amino acid deletions in the protein encoded by the RPA1 gene. In some embodiments, the decrease in the level and / or activity of RPA1 in cancer cells is the result of one or more inactivating amino acid substitutions in the protein encoded by the RPA1 gene.

[0110] In some embodiments, the increase in cGAS / STING signaling pathway activity is a result of a decrease in the level and / or activity of RAD51 in cancer cells. In some embodiments, the decrease in the level and / or activity of RAD51 in cancer cells is a result of one or more inactivating amino acid substitutions in the protein encoded by the RAD51 gene. In some embodiments, the one or more inactivating amino acid substitutions in the protein encoded by the RAD51 gene are R254* amino acid substitutions (e.g., a mutation in the RAD51 gene causing an R254* amino acid substitution to SEQ ID NO: 51). In some embodiments, the decrease in the level and / or activity of RAD51 in cancer cells is a result of RAD51 gene loss in cancer cells. In some embodiments, the decrease in the level and / or activity of RAD51 in cancer cells is a result of one or more amino acid deletions in the protein encoded by the RAD51 gene.

[0111] In some embodiments, the increased cGAS / STING signaling pathway activity is the result of increased levels and / or activity of MUS81 in the cancer cells. In some embodiments, the increased levels and / or activity of MUS81 in the cancer cells is the result of MUS81 gene amplification in the cancer cells. In some embodiments, the increased levels and / or activity of MUS81 in the cancer cells is the result of one or more activating amino acid substitutions in the protein encoded by the MUS81 gene.

[0112] In some embodiments, the increase in cGAS / STING signaling pathway activity is the result of an increase in the level and / or activity of IFI16 in cancer cells. In some embodiments, the increase in the level and / or activity of IFI16 in cancer cells is the result of IFI16 gene amplification in cancer cells. In some embodiments, the increase in the level and / or activity of IFI16 in cancer cells is the result of one or more activating amino acid substitutions in the protein encoded by the IFI16 gene.

[0113] In some embodiments, the increase in cGAS / STING signaling pathway activity is the result of an increase in the level and / or activity of cGAS in cancer cells. In some embodiments, the increase in the level and / or activity of cGAS in cancer cells is the result of cGAS gene amplification in cancer cells. In some embodiments, the increase in the level and / or activity of cGAS in cancer cells is the result of one or more activating amino acid substitutions in the protein encoded by the cGAS gene.

[0114] In some embodiments, the increased cGAS / STING signaling pathway activity is the result of increased activity of STING in the cancer cell, hi some embodiments, the increased activity of STING in the cancer cell is the result of one or more activating amino acid substitutions in the protein encoded by the STING gene.

[0115] In some embodiments, the increase in cGAS / STING signaling pathway activity is the result of the increase in the level and / or activity of DDX41 in cancer cells.In some embodiments, the increase in the level and / or activity of DDX41 in cancer cells is the result of DDX41 gene amplification in cancer cells.In some embodiments, the increase in the level and / or activity of DDX41 in cancer cells is the result of one or more activating amino acid substitutions in the protein encoded by the DDX41 gene.

[0116] In some embodiments, the increased cGAS / STING signaling pathway activity is the result of increased levels and / or activity of EXO1 in the cancer cells. In some embodiments, the increased levels and / or activity of EXO1 in the cancer cells is the result of EXO1 gene amplification in the cancer cells. In some embodiments, the increased levels and / or activity of EXO1 in the cancer cells is the result of one or more activating amino acid substitutions in the protein encoded by the EXO1 gene.

[0117] In some embodiments, the increase in cGAS / STING signaling pathway activity is the result of an increase in the level and / or activity of DNA2 in the cancer cell. In some embodiments, the increase in the level and / or activity of DNA2 in the cancer cell is the result of DNA2 gene amplification in the cancer cell. In some embodiments, the increase in the level and / or activity of DNA2 in the cancer cell is the result of one or more activating amino acid substitutions in the protein encoded by the DNA2 gene.

[0118] In some embodiments, the increase in cGAS / STING signaling pathway activity is the result of an increase in the level and / or activity of RBBP8 (CtIP) in cancer cells. In some embodiments, the increase in the level and / or activity of RBBP8 (CtIP) in cancer cells is the result of RBBP8 (CtIP) gene amplification in cancer cells. In some embodiments, the increase in the level and / or activity of RBBP8 (CtIP) in cancer cells is the result of one or more activating amino acid substitutions in the protein encoded by the RBBP8 (CtIP) gene.

[0119] In some embodiments, the increased cGAS / STING signaling pathway activity is the result of increased levels and / or activity of MRE11 in the cancer cells. In some embodiments, the increased levels and / or activity of MRE11 in the cancer cells is the result of MRE11 gene amplification in the cancer cells. In some embodiments, the increased levels and / or activity of MRE11 in the cancer cells is the result of one or more activating amino acid substitutions in the protein encoded by the MRE11 gene.

[0120] In some embodiments, the subject has been diagnosed or identified as having cancer. In some embodiments, the cancer is selected from the group consisting of renal clear cell carcinoma, papillary renal cell carcinoma, chromophobe renal cell carcinoma, uveal melanoma, tongue squamous cell carcinoma, breast cancer, osteosarcoma, and skin cancer. In some embodiments, the cancer is selected from the group consisting of renal clear cell carcinoma, uveal melanoma, tongue squamous cell carcinoma, breast cancer, and skin cancer.

[0121] In some embodiments of any of the treatment methods described herein, the method can result in a reduction in the risk of developing a comorbidity in a subject (e.g., a reduction of 1% to 99%, or any subrange of this range as described herein) (e.g., compared to the risk of developing a comorbidity in a subject having cancer cells with a similar decrease in TREX1 levels and / or activity and / or increased cGAS / STING signaling pathway activity, but who is administered a different treatment or a placebo).

[0122] Further exemplary aspects that can be used or incorporated into these methods are described herein.

[0123] Method for selecting a treatment for a subject A method of selecting a treatment for a subject in need thereof (e.g., any of the exemplary subjects described herein), comprising the steps of: (a) identifying a subject having cells (e.g., cancer cells) having one or both of: (i) a decrease in the level and / or activity of TREX1 (e.g., a decrease of about 1% to about 99%, or any subrange of this range described herein) (e.g., compared to a reference level); and (ii) an increase in cGAS / STING signaling pathway activity (e.g., an increase of 1% to 1000%, or any subrange of this range described herein) (e.g., compared to a reference level); and / or (II) an elevated level of cGAMP in serum or tumor (e.g., an increase of 1% to 1000%, or any subrange of this range described herein) (e.g., compared to a reference level); and (b) Provided herein are methods that include selecting, for an identified subject, a treatment comprising a therapeutically effective amount of a STING antagonist, or a pharma- ceutically acceptable salt, solvate, or cocrystal thereof, where the STING antagonist is a compound of any one of Formulas I-XXIV (e.g., Formulas XI-XV) or Formulas M1-M6 (e.g., Formulas M3-M6), or a compound set forth in Table C1.

[0124] A method of selecting a treatment for a subject in need thereof (e.g., any of the exemplary subjects described herein), comprising: (I) having cells (e.g., cancer cells) having one or both of: (i) a decrease in the level and / or activity of TREX1 (e.g., a decrease of about 1% to about 99%, or any subrange of this range described herein) (e.g., compared to a reference level); and (ii) an increase in cGAS / STING signaling pathway activity (e.g., an increase of 1% to 1000%, or any subrange of this range described herein) (e.g., compared to a reference level); or (II) Provided herein are methods for a subject identified as having an elevated level of cGAMP in a serum or tumor sample (e.g., an increase of 1% to 1000%, or any subrange of this range described herein) (e.g., compared to a reference level), comprising selecting a treatment comprising a therapeutically effective amount of a STING antagonist, or a pharma- ceutically acceptable salt, solvate, or cocrystal thereof, wherein the STING antagonist is a compound of any one of Formulas I-XXIV (e.g., Formulas XI-XV) or Formulas M1-M6 (e.g., Formulas M3-M6), or a compound set forth in Table C1.

[0125] In some embodiments, the subject is identified as having cancer cells with a decreased level and / or activity of TREX1. In some embodiments, the subject is identified as having cancer cells with an increased cGAS / STING signaling pathway activity. In some embodiments, the subject is identified as having cancer cells with both (i) a decreased level and / or activity of TREX1 and (ii) an increased cGAS / STING signaling pathway activity (e.g., an increase of 1% to 1000%, or any subrange of this range described herein) (e.g., compared to a reference level), or the subject is identified as having an elevated level of cGAMP (e.g., an increase of 1% to 1000%, or any subrange of this range described herein) (e.g., compared to a reference level) in a serum sample or tumor sample from the patient. In some embodiments, the subject is identified as having cancer cells with a decreased level of TREX1. In some embodiments, the level of TREX1 is the level of TREX1 protein in the cancer cells. In some embodiments, identifying the subject as having cancer cells with a decreased level of TREX1 comprises detecting a decreased level of TREX1 protein in the cancer cells. In some embodiments, the level of TREX1 is the level of TREX1 mRNA in the cancer cells. In some embodiments, identifying a subject as having cancer cells with a decreased level of TREX1 comprises detecting a decreased level of TREX1 mRNA in the cancer cells.

[0126] In some embodiments, the reduced level and / or activity of TREX1 is a result of TREX1 gene loss in the cancer cells. In some embodiments, the TREX1 gene loss is a loss of one allele of the TREX1 gene. In some embodiments, the TREX1 gene loss is a loss of both alleles of the TREX1 gene. In some embodiments, identifying the subject as having cancer cells with reduced level and / or activity of TREX1 comprises detecting TREX1 gene loss in the cancer cells. In some embodiments, the reduced level and / or activity of TREX1 is a result of one or more amino acid deletions in a protein encoded by the TREX1 gene in the cancer cells. In some embodiments, identifying the subject as having cancer cells with reduced level and / or activity of TREX1 comprises detecting one or more amino acid deletions in a protein encoded by the TREX1 gene in the cancer cells. In some embodiments, the reduced level and / or activity of TREX1 is a result of one or more inactivating amino acid substitutions in a protein encoded by the TREX1 gene in the cancer cells. In some embodiments, identifying a subject as having cancer cells with reduced expression and / or activity of TREX1 comprises detecting one or more inactivating amino acid substitutions in a protein encoded by the TREX1 gene in the cancer cells.

[0127] In some embodiments, the increased cGAS / STING signaling pathway activity is a result of a decreased level and / or activity of BRCA1 in the cancer cell. In some embodiments, the decreased level and / or activity of BRCA1 in the cancer cell is a result of a frameshift mutation in the BRCA1 gene. In some embodiments, the frameshift mutation in the BRCA1 gene is an E111Gfs*3 frameshift insertion (e.g., a mutation in the BRCA1 gene causing an E111Gfs*3 frameshift insertion relative to SEQ ID NO: 15). In some embodiments, the decreased level and / or activity of BRCA1 in the cancer cell is a result of a BRCA1 gene loss in the cancer cell. In some embodiments, the decreased level and / or activity of BRCA1 in the cancer cell is a result of one or more amino acid deletions in the protein encoded by the BRCA1 gene. In some embodiments, the decreased level and / or activity of BRCA1 in the cancer cell is a result of one or more inactivating amino acid substitutions in the protein encoded by the BRCA1 gene.

[0128] In some embodiments, the increased cGAS / STING signaling pathway activity is a result of a decreased level and / or activity of the BRCA2 gene. In some embodiments, the decreased level and / or activity of BRCA2 in the cancer cell is a result of a frameshift mutation in the BRCA2 gene. In some embodiments, the frameshift mutation in the BRCA2 gene is a N1784Kfs*3 frameshift insertion (e.g., a mutation in the BRCA2 gene causing a N1784Kfs*3 frameshift insertion relative to SEQ ID NO: 25). In some embodiments, the decreased level and / or activity of BRCA2 in the cancer cell is a result of a BRCA2 gene loss in the cancer cell. In some embodiments, the decreased level and / or activity of BRCA2 in the cancer cell is a result of one or more amino acid deletions in the protein encoded by the BRCA2 gene. In some embodiments, the decreased level and / or activity of BRCA2 in the cancer cell is a result of one or more inactivating amino acid substitutions in the protein encoded by the BRCA2 gene.

[0129] In some embodiments, the increase in cGAS / STING signaling pathway activity is the result of a decrease in the level and / or activity of SAMHD1 in cancer cells. In some embodiments, the decrease in the level and / or activity of SAMHD1 in cancer cells is the result of one or more inactivating amino acid substitutions in the protein encoded by the SAMHD1 gene in cancer cells. In some embodiments, the one or more inactivating amino acid substitutions in the protein encoded by the SAMHD1 gene are V133I amino acid substitutions (e.g., a mutation in the SAMHD1 gene that causes a V133I amino acid substitution to SEQ ID NO: 27). In some embodiments, the decrease in the level and / or activity of SAMHD1 in cancer cells is the result of SAMHD1 gene loss in cancer cells. In some embodiments, the decrease in the level and / or activity of SAMHD1 in cancer cells is the result of one or more amino acid deletions in the protein encoded by the SAMHD1 gene.

[0130] In some embodiments, the increase in cGAS / STING signaling pathway activity is the result of a decrease in the level and / or activity of DNASE2 in cancer cells. In some embodiments, the decrease in the level and / or activity of DNASE2 in cancer cells is the result of one or more inactivating amino acid substitutions in the protein encoded by the DNASE2 gene in cancer cells. In some embodiments, the one or more inactivating amino acid substitutions in the protein encoded by the DNASE2 gene are R314W amino acid substitutions (e.g., a mutation in the DNASE2 gene that causes an R314W amino acid substitution to SEQ ID NO: 33). In some embodiments, the decrease in the level and / or activity of DNASE2 in cancer cells is the result of DNASE2 gene loss in cancer cells. In some embodiments, the decrease in the level and / or activity of DNASE2 in cancer cells is the result of one or more amino acid deletions in the protein encoded by the DNASE2 gene.

[0131] In some embodiments, the increased cGAS / STING signaling pathway activity is the result of a decreased level and / or activity of BLM in cancer cells. In some embodiments, the decreased level and / or activity of BLM in cancer cells is the result of a frameshift mutation in the BLM gene. In some embodiments, the frameshift mutation in the BLM gene is a N515Mfs*16 frameshift deletion (e.g., a mutation in the BLM gene causing a N515Mfs*16 frameshift deletion relative to SEQ ID NO: 37). In some embodiments, the decreased level and / or activity of BLM in cancer cells is the result of a BLM gene loss in cancer cells. In some embodiments, the decreased level and / or activity of BLM in cancer cells is the result of one or more amino acid deletions in the protein encoded by the BLM gene. In some embodiments, the decreased level and / or activity of BLM in cancer cells is the result of one or more inactivating amino acid substitutions in the protein encoded by the BLM gene.

[0132] In some embodiments, the increase in cGAS / STING signaling pathway activity is a result of a decrease in the level and / or activity of PARP1 in cancer cells. In some embodiments, the decrease in the level and / or activity of PARP1 in cancer cells is a result of a frameshift mutation in the PARP1 gene. In some embodiments, the frameshift mutation in the PARP1 gene is a S507Afs*17 frameshift deletion (e.g., a mutation in the PARP1 gene causing a S507Afs*17 frameshift deletion relative to SEQ ID NO: 43). In some embodiments, the decrease in the level and / or activity of PARP1 in cancer cells is a result of PARP1 gene loss in cancer cells. In some embodiments, the decrease in the level and / or activity of PARP1 in cancer cells is a result of one or more amino acid deletions in the protein encoded by the PARP1 gene. In some embodiments, the decrease in the level and / or activity of PARP1 in cancer cells is a result of one or more inactivating amino acid substitutions in the protein encoded by the PARP1 gene.

[0133] In some embodiments, the increase in cGAS / STING signaling pathway activity is the result of a decrease in the level and / or activity of RPA1 in cancer cells. In some embodiments, the decrease in the level and / or activity of RPA1 in cancer cells is the result of a mutation that causes aberrant RPA1 mRNA splicing in cancer cells. In some embodiments, the mutation that causes aberrant RPA1 mRNA splicing in cancer cells is a X12 splice mutation. In some embodiments, the decrease in the level and / or activity of RPA1 in cancer cells is the result of RPA1 gene loss in cancer cells. In some embodiments, the decrease in the level and / or activity of RPA1 in cancer cells is the result of one or more amino acid deletions in the protein encoded by the RPA1 gene. In some embodiments, the decrease in the level and / or activity of RPA1 in cancer cells is the result of one or more inactivating amino acid substitutions in the protein encoded by the RPA1 gene.

[0134] In some embodiments, the increase in cGAS / STING signaling pathway activity is a result of a decrease in the level and / or activity of RAD51 in cancer cells. In some embodiments, the decrease in the level and / or activity of RAD51 in cancer cells is a result of one or more inactivating amino acid substitutions in the protein encoded by the RAD51 gene. In some embodiments, the one or more inactivating amino acid substitutions in the protein encoded by the RAD51 gene are R254* amino acid substitutions (e.g., a mutation in the RAD51 gene causing an R254* amino acid substitution to SEQ ID NO: 51). In some embodiments, the decrease in the level and / or activity of RAD51 in cancer cells is a result of RAD51 gene loss in cancer cells. In some embodiments, the decrease in the level and / or activity of RAD51 in cancer cells is a result of one or more amino acid deletions in the protein encoded by the RAD51 gene.

[0135] In some embodiments, the increased cGAS / STING signaling pathway activity is the result of increased levels and / or activity of MUS81 in the cancer cells. In some embodiments, the increased levels and / or activity of MUS81 in the cancer cells is the result of MUS81 gene amplification in the cancer cells. In some embodiments, the increased levels and / or activity of MUS81 in the cancer cells is the result of one or more activating amino acid substitutions in the protein encoded by the MUS81 gene.

[0136] In some embodiments, the increase in cGAS / STING signaling pathway activity is the result of an increase in the level and / or activity of IFI16 in cancer cells. In some embodiments, the increase in the level and / or activity of IFI16 in cancer cells is the result of IFI16 gene amplification in cancer cells. In some embodiments, the increase in the level and / or activity of IFI16 in cancer cells is the result of one or more activating amino acid substitutions in the protein encoded by the IFI16 gene.

[0137] In some embodiments, the increase in cGAS / STING signaling pathway activity is the result of an increase in the level and / or activity of cGAS in cancer cells. In some embodiments, the increase in the level and / or activity of cGAS in cancer cells is the result of cGAS gene amplification in cancer cells. In some embodiments, the increase in the level and / or activity of cGAS in cancer cells is the result of one or more activating amino acid substitutions in the protein encoded by the cGAS gene.

[0138] In some embodiments, the increased cGAS / STING signaling pathway activity is the result of increased activity of STING in the cancer cell, hi some embodiments, the increased activity of STING in the cancer cell is the result of one or more activating amino acid substitutions in the protein encoded by the STING gene.

[0139] In some embodiments, the increase in cGAS / STING signaling pathway activity is the result of the increase in the level and / or activity of DDX41 in cancer cells.In some embodiments, the increase in the level and / or activity of DDX41 in cancer cells is the result of DDX41 gene amplification in cancer cells.In some embodiments, the increase in the level and / or activity of DDX41 in cancer cells is the result of one or more activating amino acid substitutions in the protein encoded by the DDX41 gene.

[0140] In some embodiments, the increased cGAS / STING signaling pathway activity is the result of increased levels and / or activity of EXO1 in the cancer cells. In some embodiments, the increased levels and / or activity of EXO1 in the cancer cells is the result of EXO1 gene amplification in the cancer cells. In some embodiments, the increased levels and / or activity of EXO1 in the cancer cells is the result of one or more activating amino acid substitutions in the protein encoded by the EXO1 gene.

[0141] In some embodiments, the increase in cGAS / STING signaling pathway activity is the result of an increase in the level and / or activity of DNA2 in the cancer cell. In some embodiments, the increase in the level and / or activity of DNA2 in the cancer cell is the result of DNA2 gene amplification in the cancer cell. In some embodiments, the increase in the level and / or activity of DNA2 in the cancer cell is the result of one or more activating amino acid substitutions in the protein encoded by the DNA2 gene.

[0142] In some embodiments, the increase in cGAS / STING signaling pathway activity is the result of an increase in the level and / or activity of RBBP8 (CtIP) in cancer cells. In some embodiments, the increase in the level and / or activity of RBBP8 (CtIP) in cancer cells is the result of RBBP8 (CtIP) gene amplification in cancer cells. In some embodiments, the increase in the level and / or activity of RBBP8 (CtIP) in cancer cells is the result of one or more activating amino acid substitutions in the protein encoded by the RBBP8 (CtIP) gene.

[0143] In some embodiments, the increased cGAS / STING signaling pathway activity is the result of increased levels and / or activity of MRE11 in the cancer cells. In some embodiments, the increased levels and / or activity of MRE11 in the cancer cells is the result of MRE11 gene amplification in the cancer cells. In some embodiments, the increased levels and / or activity of MRE11 in the cancer cells is the result of one or more activating amino acid substitutions in the protein encoded by the MRE11 gene.

[0144] In some embodiments, the subject has been diagnosed or identified as having cancer. In some embodiments, the cancer is selected from the group consisting of renal clear cell carcinoma, papillary renal cell carcinoma, chromophobe renal cell carcinoma, uveal melanoma, tongue squamous cell carcinoma, breast cancer, osteosarcoma, and skin cancer. In some embodiments, the method further comprises administering the selected treatment to the subject. In some embodiments, the cancer is selected from the group consisting of renal clear cell carcinoma, uveal melanoma, tongue squamous cell carcinoma, breast cancer, and skin cancer. In some embodiments, the method further comprises administering the selected treatment to the subject.

[0145] Some embodiments of any of the methods described herein may further include recording the selected treatment in the subject's clinical record (e.g., a computer-readable medium). Some embodiments of any of the methods described herein may further include administering one or more doses (e.g., at least 2 doses, at least 4 doses, at least 6 doses, at least 8 doses, at least 10 doses) of the selected treatment to the identified subject.

[0146] Further exemplary aspects that can be used or incorporated into these methods are described herein.

[0147] Methods for selecting subjects for treatment A method of selecting a subject for treatment, comprising the steps of: (a) identifying (I) cells (e.g., cancer cells) having one or both of: (i) a decrease in the level and / or activity of TREX1 (e.g., a decrease of about 1% to about 99%, or any subrange of this range described herein) (e.g., compared to a reference level); and (ii) an increase in cGAS / STING signaling pathway activity (e.g., an increase of 1% to 1000%, or any subrange of this range described herein) (e.g., compared to a reference level); and / or (II) a subject (e.g., any subject described herein) having an elevated level of cGAMP in a serum sample or tumor sample (e.g., an increase of 1% to 1000%, or any subrange of this range described herein) (e.g., compared to a reference level); and (b) Also provided herein are methods comprising selecting the identified subject for treatment with a therapeutically effective amount of a STING antagonist, or a pharma- ceutically acceptable salt, solvate, or cocrystal thereof, wherein the STING antagonist is a compound of any one of Formulas I-XXIV (e.g., Formulas XI-XV) or Formulas M1-M6 (e.g., Formulas M3-M6), or a compound set forth in Table C1.

[0148] 1. A method of selecting a subject for treatment, the method comprising the steps of: (I) selecting a subject for treatment with a therapeutically effective amount of a STING antagonist, or a pharma- ceutically acceptable salt, solvate, or cocrystal thereof, the subject having cells (e.g., cancer cells) that have one or both of: (i) a decrease in a level and / or activity of TREX1 (e.g., a decrease of about 1% to about 99%, or any subrange of this range described herein) (e.g., compared to a reference level); and (ii) an increase in a cGAS / STING signaling pathway activity (e.g., an increase of 1% to 1000%, or any subrange of this range described herein) (e.g., compared to a reference level); and / or (II) Also provided herein are methods that include selecting a subject (e.g., any subject described herein) identified as having an elevated level of cGAMP in a serum sample or a tumor sample (e.g., an increase of 1% to 1000%, or any subrange of this range described herein) (e.g., compared to a reference level), wherein the STING antagonist is a compound of any one of Formulas I-XXIV (e.g., Formulas XI-XV) or Formulas M1-M6 (e.g., Formulas M3-M6), or a compound set forth in Table C1.

[0149] In some embodiments, the subject is identified as having cancer cells with a decreased level and / or activity of TREX1. In some embodiments, the subject is identified as having an elevated level of cGAMP in the serum sample or tumor sample compared to a reference sample. In some embodiments, the subject is identified as having cancer cells with an increased cGAS / STING signaling pathway activity. In some embodiments, the subject is identified as having cancer cells with both (i) a decreased level and / or activity of TREX1 and (ii) an increased cGAS / STING signaling pathway activity (e.g., an increase of 1% to 1000%, or any subrange of this range described herein) (e.g., compared to a reference level), or the subject is identified as having an elevated level of cGAMP (e.g., an increase of 1% to 1000%, or any subrange of this range described herein) (e.g., compared to a reference level) in the serum sample or tumor sample. In some embodiments, the subject is identified as having cancer cells with a decreased level of TREX1. In some embodiments, the level of TREX1 is the level of TREX1 protein in the cancer cells. In some embodiments, identifying a subject as having cancer cells with a reduced level of TREX1 comprises detecting a reduced level of TREX1 protein in the cancer cells. In some embodiments, the level of TREX1 is the level of TREX1 mRNA in the cancer cells. In some embodiments, identifying a subject as having cancer cells with a reduced level of TREX1 comprises detecting a reduced level of TREX1 mRNA in the cancer cells.

[0150] In some embodiments, the reduced level and / or activity of TREX1 is a result of TREX1 gene loss in the cancer cells. In some embodiments, the TREX1 gene loss is a loss of one allele of the TREX1 gene. In some embodiments, the TREX1 gene loss is a loss of both alleles of the TREX1 gene. In some embodiments, identifying the subject as having cancer cells with reduced level and / or activity of TREX1 comprises detecting TREX1 gene loss in the cancer cells. In some embodiments, the reduced level and / or activity of TREX1 is a result of one or more amino acid deletions in a protein encoded by the TREX1 gene in the cancer cells. In some embodiments, identifying the subject as having cancer cells with reduced level and / or activity of TREX1 comprises detecting one or more amino acid deletions in a protein encoded by the TREX1 gene in the cancer cells. In some embodiments, the reduced level and / or activity of TREX1 is a result of one or more inactivating amino acid substitutions in a protein encoded by the TREX1 gene in the cancer cells. In some embodiments, identifying a subject as having cancer cells with reduced expression and / or activity of TREX1 comprises detecting one or more inactivating amino acid substitutions in a protein encoded by the TREX1 gene in the cancer cells.

[0151] In some embodiments, the increased cGAS / STING signaling pathway activity is a result of a decreased level and / or activity of BRCA1 in the cancer cell. In some embodiments, the decreased level and / or activity of BRCA1 in the cancer cell is a result of a frameshift mutation in the BRCA1 gene. In some embodiments, the frameshift mutation in the BRCA1 gene is an E111Gfs*3 frameshift insertion (e.g., a mutation in the BRCA1 gene causing an E111Gfs*3 frameshift insertion relative to SEQ ID NO: 15). In some embodiments, the decreased level and / or activity of BRCA1 in the cancer cell is a result of a BRCA1 gene loss in the cancer cell. In some embodiments, the decreased level and / or activity of BRCA1 in the cancer cell is a result of one or more amino acid deletions in the protein encoded by the BRCA1 gene. In some embodiments, the decreased level and / or activity of BRCA1 in the cancer cell is a result of one or more inactivating amino acid substitutions in the protein encoded by the BRCA1 gene.

[0152] In some embodiments, the increased cGAS / STING signaling pathway activity is a result of a decreased level and / or activity of the BRCA2 gene. In some embodiments, the decreased level and / or activity of BRCA2 in the cancer cell is a result of a frameshift mutation in the BRCA2 gene. In some embodiments, the frameshift mutation in the BRCA2 gene is a N1784Kfs*3 frameshift insertion (e.g., a mutation in the BRCA2 gene causing a N1784Kfs*3 frameshift insertion relative to SEQ ID NO: 25). In some embodiments, the decreased level and / or activity of BRCA2 in the cancer cell is a result of a BRCA2 gene loss in the cancer cell. In some embodiments, the decreased level and / or activity of BRCA2 in the cancer cell is a result of one or more amino acid deletions in the protein encoded by the BRCA2 gene. In some embodiments, the decreased level and / or activity of BRCA2 in the cancer cell is a result of one or more inactivating amino acid substitutions in the protein encoded by the BRCA2 gene.

[0153] In some embodiments, the increase in cGAS / STING signaling pathway activity is the result of a decrease in the level and / or activity of SAMHD1 in cancer cells. In some embodiments, the decrease in the level and / or activity of SAMHD1 in cancer cells is the result of one or more inactivating amino acid substitutions in the protein encoded by the SAMHD1 gene in cancer cells. In some embodiments, the one or more inactivating amino acid substitutions in the protein encoded by the SAMHD1 gene are V133I amino acid substitutions (e.g., a mutation in the SAMHD1 gene that causes a V133I amino acid substitution to SEQ ID NO: 27). In some embodiments, the decrease in the level and / or activity of SAMHD1 in cancer cells is the result of SAMHD1 gene loss in cancer cells. In some embodiments, the decrease in the level and / or activity of SAMHD1 in cancer cells is the result of one or more amino acid deletions in the protein encoded by the SAMHD1 gene.

[0154] In some embodiments, the increase in cGAS / STING signaling pathway activity is the result of a decrease in the level and / or activity of DNASE2 in cancer cells. In some embodiments, the decrease in the level and / or activity of DNASE2 in cancer cells is the result of one or more inactivating amino acid substitutions in the protein encoded by the DNASE2 gene in cancer cells. In some embodiments, the one or more inactivating amino acid substitutions in the protein encoded by the DNASE2 gene are R314W amino acid substitutions (e.g., a mutation in the DNASE2 gene that causes an R314W amino acid substitution to SEQ ID NO: 33). In some embodiments, the decrease in the level and / or activity of DNASE2 in cancer cells is the result of DNASE2 gene loss in cancer cells. In some embodiments, the decrease in the level and / or activity of DNASE2 in cancer cells is the result of one or more amino acid deletions in the protein encoded by the DNASE2 gene.

[0155] In some embodiments, the increased cGAS / STING signaling pathway activity is the result of a decreased level and / or activity of BLM in cancer cells. In some embodiments, the decreased level and / or activity of BLM in cancer cells is the result of a frameshift mutation in the BLM gene. In some embodiments, the frameshift mutation in the BLM gene is a N515Mfs*16 frameshift deletion (e.g., a mutation in the BLM gene causing a N515Mfs*16 frameshift deletion relative to SEQ ID NO: 37). In some embodiments, the decreased level and / or activity of BLM in cancer cells is the result of a BLM gene loss in cancer cells. In some embodiments, the decreased level and / or activity of BLM in cancer cells is the result of one or more amino acid deletions in the protein encoded by the BLM gene. In some embodiments, the decreased level and / or activity of BLM in cancer cells is the result of one or more inactivating amino acid substitutions in the protein encoded by the BLM gene.

[0156] In some embodiments, the increase in cGAS / STING signaling pathway activity is a result of a decrease in the level and / or activity of PARP1 in cancer cells. In some embodiments, the decrease in the level and / or activity of PARP1 in cancer cells is a result of a frameshift mutation in the PARP1 gene. In some embodiments, the frameshift mutation in the PARP1 gene is a S507Afs*17 frameshift deletion (e.g., a mutation in the PARP1 gene causing a S507Afs*17 frameshift deletion relative to SEQ ID NO: 43). In some embodiments, the decrease in the level and / or activity of PARP1 in cancer cells is a result of PARP1 gene loss in cancer cells. In some embodiments, the decrease in the level and / or activity of PARP1 in cancer cells is a result of one or more amino acid deletions in the protein encoded by the PARP1 gene. In some embodiments, the decrease in the level and / or activity of PARP1 in cancer cells is a result of one or more inactivating amino acid substitutions in the protein encoded by the PARP1 gene.

[0157] In some embodiments, the increase in cGAS / STING signaling pathway activity is the result of a decrease in the level and / or activity of RPA1 in cancer cells. In some embodiments, the decrease in the level and / or activity of RPA1 in cancer cells is the result of a mutation that causes aberrant RPA1 mRNA splicing in cancer cells. In some embodiments, the mutation that causes aberrant RPA1 mRNA splicing in cancer cells is a X12 splice mutation. In some embodiments, the decrease in the level and / or activity of RPA1 in cancer cells is the result of RPA1 gene loss in cancer cells. In some embodiments, the decrease in the level and / or activity of RPA1 in cancer cells is the result of one or more amino acid deletions in the protein encoded by the RPA1 gene. In some embodiments, the decrease in the level and / or activity of RPA1 in cancer cells is the result of one or more inactivating amino acid substitutions in the protein encoded by the RPA1 gene.

[0158] In some embodiments, the increase in cGAS / STING signaling pathway activity is a result of a decrease in the level and / or activity of RAD51 in cancer cells. In some embodiments, the decrease in the level and / or activity of RAD51 in cancer cells is a result of one or more inactivating amino acid substitutions in the protein encoded by the RAD51 gene. In some embodiments, the one or more inactivating amino acid substitutions in the protein encoded by the RAD51 gene are R254* amino acid substitutions (e.g., a mutation in the RAD51 gene causing an R254* amino acid substitution to SEQ ID NO: 51). In some embodiments, the decrease in the level and / or activity of RAD51 in cancer cells is a result of RAD51 gene loss in cancer cells. In some embodiments, the decrease in the level and / or activity of RAD51 in cancer cells is a result of one or more amino acid deletions in the protein encoded by the RAD51 gene.

[0159] In some embodiments, the increased cGAS / STING signaling pathway activity is the result of increased levels and / or activity of MUS81 in the cancer cells. In some embodiments, the increased levels and / or activity of MUS81 in the cancer cells is the result of MUS81 gene amplification in the cancer cells. In some embodiments, the increased levels and / or activity of MUS81 in the cancer cells is the result of one or more activating amino acid substitutions in the protein encoded by the MUS81 gene.

[0160] In some embodiments, the increase in cGAS / STING signaling pathway activity is the result of an increase in the level and / or activity of IFI16 in cancer cells. In some embodiments, the increase in the level and / or activity of IFI16 in cancer cells is the result of IFI16 gene amplification in cancer cells. In some embodiments, the increase in the level and / or activity of IFI16 in cancer cells is the result of one or more activating amino acid substitutions in the protein encoded by the IFI16 gene.

[0161] In some embodiments, the increase in cGAS / STING signaling pathway activity is the result of an increase in the level and / or activity of cGAS in cancer cells. In some embodiments, the increase in the level and / or activity of cGAS in cancer cells is the result of cGAS gene amplification in cancer cells. In some embodiments, the increase in the level and / or activity of cGAS in cancer cells is the result of one or more activating amino acid substitutions in the protein encoded by the cGAS gene.

[0162] In some embodiments, the increased cGAS / STING signaling pathway activity is the result of increased activity of STING in the cancer cell, hi some embodiments, the increased activity of STING in the cancer cell is the result of one or more activating amino acid substitutions in the protein encoded by the STING gene.

[0163] In some embodiments, the increase in cGAS / STING signaling pathway activity is the result of the increase in the level and / or activity of DDX41 in cancer cells.In some embodiments, the increase in the level and / or activity of DDX41 in cancer cells is the result of DDX41 gene amplification in cancer cells.In some embodiments, the increase in the level and / or activity of DDX41 in cancer cells is the result of one or more activating amino acid substitutions in the protein encoded by the DDX41 gene.

[0164] In some embodiments, the increased cGAS / STING signaling pathway activity is the result of increased levels and / or activity of EXO1 in the cancer cells. In some embodiments, the increased levels and / or activity of EXO1 in the cancer cells is the result of EXO1 gene amplification in the cancer cells. In some embodiments, the increased levels and / or activity of EXO1 in the cancer cells is the result of one or more activating amino acid substitutions in the protein encoded by the EXO1 gene.

[0165] In some embodiments, the increase in cGAS / STING signaling pathway activity is the result of an increase in the level and / or activity of DNA2 in the cancer cell. In some embodiments, the increase in the level and / or activity of DNA2 in the cancer cell is the result of DNA2 gene amplification in the cancer cell. In some embodiments, the increase in the level and / or activity of DNA2 in the cancer cell is the result of one or more activating amino acid substitutions in the protein encoded by the DNA2 gene.

[0166] In some embodiments, the increase in cGAS / STING signaling pathway activity is the result of an increase in the level and / or activity of RBBP8 (CtIP) in cancer cells. In some embodiments, the increase in the level and / or activity of RBBP8 (CtIP) in cancer cells is the result of RBBP8 (CtIP) gene amplification in cancer cells. In some embodiments, the increase in the level and / or activity of RBBP8 (CtIP) in cancer cells is the result of one or more activating amino acid substitutions in the protein encoded by the RBBP8 (CtIP) gene.

[0167] In some embodiments, the increased cGAS / STING signaling pathway activity is the result of increased levels and / or activity of MRE11 in the cancer cells. In some embodiments, the increased levels and / or activity of MRE11 in the cancer cells is the result of MRE11 gene amplification in the cancer cells. In some embodiments, the increased levels and / or activity of MRE11 in the cancer cells is the result of one or more activating amino acid substitutions in the protein encoded by the MRE11 gene.

[0168] In some embodiments, the subject has been diagnosed or identified as having cancer. In some embodiments, the cancer is selected from the group consisting of renal clear cell carcinoma, papillary renal cell carcinoma, chromophobe renal cell carcinoma, uveal melanoma, tongue squamous cell carcinoma, breast cancer, osteosarcoma, and skin cancer. In some embodiments, the cancer is selected from the group consisting of renal clear cell carcinoma, uveal melanoma, tongue squamous cell carcinoma, breast cancer, and skin cancer.

[0169] Further exemplary aspects that can be used or incorporated into these methods are described herein.

[0170] Methods for selecting subjects for participation in clinical trials A method of selecting a subject (e.g., any of the exemplary subjects described herein) for participation in a clinical trial, comprising the steps of: (a) identifying (I) a subject having one or both of: (i) a decrease in the level and / or activity of TREX1 (e.g., a decrease of about 1% to about 99%, or any subrange of this range described herein) (e.g., compared to a reference level); and (ii) an increase in cGAS / STING signaling pathway activity (e.g., an increase of 1% to 1000%, or any subrange of this range described herein) (e.g., compared to a reference level); and / or (II) an elevated level of cGAMP in a serum sample or tumor sample (e.g., an increase of 1% to 1000%, or any subrange of this range described herein) (e.g., compared to a reference level); and (b) Provided herein are methods comprising selecting the identified subject for participation in a clinical trial involving administration of a treatment comprising a therapeutically effective amount of a STING antagonist, or a pharma- ceutically acceptable salt, solvate, or cocrystal thereof, where the STING antagonist is a compound of any one of Formulas I-XXIV (e.g., Formulas XI-XV) or Formulas M1-M6 (e.g., Formulas M3-M6), or a compound set forth in Table C1.

[0171] A method of selecting a subject (e.g., any of the exemplary subjects described herein) for participation in a clinical trial comprising administration of a treatment comprising a therapeutically effective amount of a STING antagonist, or a pharma- ceutically acceptable salt, solvate, or cocrystal thereof, comprising: (I) selecting a subject having cells (e.g., cancer cells) having one or both of: (i) a decrease in TREX1 level and / or activity (e.g., a decrease of about 1% to about 99%, or any subrange of this range described herein) (e.g., compared to a reference level); and / or (ii) an increase in cGAS / STING signaling pathway activity (e.g., an increase of 1% to 1000%, or any subrange of this range described herein) (e.g., compared to a reference level); and / or (II) selecting a subject (e.g., any of the exemplary subjects described herein) for participation in a clinical trial comprising administration of a treatment comprising a therapeutically effective amount of a STING antagonist, or a pharma- ceutical acceptable salt, solvate, or cocrystal thereof; Also provided herein are methods that include selecting a subject identified as having an elevated level of cGAMP in a serum sample or a tumor sample (e.g., an increase of 1% to 1000%, or any subrange of this range described herein) (e.g., compared to a reference level), wherein the STING antagonist is a compound of any one of Formulas I-XXIV (e.g., Formulas XI-XV) or Formulas M1-M6 (e.g., Formulas M3-M6), or a compound set forth in Table C1.

[0172] In some embodiments, the subject is identified as having cancer cells with a decreased level and / or activity of TREX1. In some embodiments, the subject is identified as having an elevated level of cGAMP in a serum sample or tumor sample. In some embodiments, the subject is identified as having cancer cells with an increased cGAS / STING signaling pathway activity. In some embodiments, the subject is identified as having cancer cells with both (i) a decreased level and / or activity of TREX1 and (ii) an increased cGAS / STING signaling pathway activity (e.g., an increase of 1% to 1000%, or any subrange of this range described herein) (e.g., compared to a reference level), or the subject is identified as having an increased level of cGAMP (e.g., an increase of 1% to 1000%, or any subrange of this range described herein) (e.g., compared to a reference level) in a serum sample or tumor sample. In some embodiments, the subject is identified as having cancer cells with a decreased level of TREX1. In some embodiments, the level of TREX1 is the level of TREX1 protein in the cancer cells. In some embodiments, identifying a subject as having cancer cells with a reduced level of TREX1 comprises detecting a reduced level of TREX1 protein in the cancer cells. In some embodiments, the level of TREX1 is the level of TREX1 mRNA in the cancer cells. In some embodiments, identifying a subject as having cancer cells with a reduced level of TREX1 comprises detecting a reduced level of TREX1 mRNA in the cancer cells.

[0173] In some embodiments, the reduced level and / or activity of TREX1 is a result of TREX1 gene loss in the cancer cells. In some embodiments, the TREX1 gene loss is a loss of one allele of the TREX1 gene. In some embodiments, the TREX1 gene loss is a loss of both alleles of the TREX1 gene. In some embodiments, identifying the subject as having cancer cells with reduced level and / or activity of TREX1 comprises detecting TREX1 gene loss in the cancer cells. In some embodiments, the reduced level and / or activity of TREX1 is a result of one or more amino acid deletions in a protein encoded by the TREX1 gene in the cancer cells. In some embodiments, identifying the subject as having cancer cells with reduced level and / or activity of TREX1 comprises detecting one or more amino acid deletions in a protein encoded by the TREX1 gene in the cancer cells. In some embodiments, the reduced level and / or activity of TREX1 is a result of one or more inactivating amino acid substitutions in a protein encoded by the TREX1 gene in the cancer cells. In some embodiments, identifying a subject as having cancer cells with reduced expression and / or activity of TREX1 comprises detecting one or more inactivating amino acid substitutions in a protein encoded by the TREX1 gene in the cancer cells.

[0174] In some embodiments, the increased cGAS / STING signaling pathway activity is a result of a decreased level and / or activity of BRCA1 in the cancer cell. In some embodiments, the decreased level and / or activity of BRCA1 in the cancer cell is a result of a frameshift mutation in the BRCA1 gene. In some embodiments, the frameshift mutation in the BRCA1 gene is an E111Gfs*3 frameshift insertion (e.g., a mutation in the BRCA1 gene causing an E111Gfs*3 frameshift insertion relative to SEQ ID NO: 15). In some embodiments, the decreased level and / or activity of BRCA1 in the cancer cell is a result of a BRCA1 gene loss in the cancer cell. In some embodiments, the decreased level and / or activity of BRCA1 in the cancer cell is a result of one or more amino acid deletions in the protein encoded by the BRCA1 gene. In some embodiments, the decreased level and / or activity of BRCA1 in the cancer cell is a result of one or more inactivating amino acid substitutions in the protein encoded by the BRCA1 gene.

[0175] In some embodiments, the increased cGAS / STING signaling pathway activity is a result of a decreased level and / or activity of the BRCA2 gene. In some embodiments, the decreased level and / or activity of BRCA2 in the cancer cell is a result of a frameshift mutation in the BRCA2 gene. In some embodiments, the frameshift mutation in the BRCA2 gene is a N1784Kfs*3 frameshift insertion (e.g., a mutation in the BRCA2 gene causing a N1784Kfs*3 frameshift insertion relative to SEQ ID NO: 25). In some embodiments, the decreased level and / or activity of BRCA2 in the cancer cell is a result of a BRCA2 gene loss in the cancer cell. In some embodiments, the decreased level and / or activity of BRCA2 in the cancer cell is a result of one or more amino acid deletions in the protein encoded by the BRCA2 gene. In some embodiments, the decreased level and / or activity of BRCA2 in the cancer cell is a result of one or more inactivating amino acid substitutions in the protein encoded by the BRCA2 gene.

[0176] In some embodiments, the increase in cGAS / STING signaling pathway activity is the result of a decrease in the level and / or activity of SAMHD1 in cancer cells. In some embodiments, the decrease in the level and / or activity of SAMHD1 in cancer cells is the result of one or more inactivating amino acid substitutions in the protein encoded by the SAMHD1 gene in cancer cells. In some embodiments, the one or more inactivating amino acid substitutions in the protein encoded by the SAMHD1 gene are V133I amino acid substitutions (e.g., a mutation in the SAMHD1 gene that causes a V133I amino acid substitution to SEQ ID NO: 27). In some embodiments, the decrease in the level and / or activity of SAMHD1 in cancer cells is the result of SAMHD1 gene loss in cancer cells. In some embodiments, the decrease in the level and / or activity of SAMHD1 in cancer cells is the result of one or more amino acid deletions in the protein encoded by the SAMHD1 gene.

[0177] In some embodiments, the increase in cGAS / STING signaling pathway activity is the result of a decrease in the level and / or activity of DNASE2 in cancer cells. In some embodiments, the decrease in the level and / or activity of DNASE2 in cancer cells is the result of one or more inactivating amino acid substitutions in the protein encoded by the DNASE2 gene in cancer cells. In some embodiments, the one or more inactivating amino acid substitutions in the protein encoded by the DNASE2 gene are R314W amino acid substitutions (e.g., a mutation in the DNASE2 gene that causes an R314W amino acid substitution to SEQ ID NO: 33). In some embodiments, the decrease in the level and / or activity of DNASE2 in cancer cells is the result of DNASE2 gene loss in cancer cells. In some embodiments, the decrease in the level and / or activity of DNASE2 in cancer cells is the result of one or more amino acid deletions in the protein encoded by the DNASE2 gene.

[0178] In some embodiments, the increased cGAS / STING signaling pathway activity is the result of a decreased level and / or activity of BLM in cancer cells. In some embodiments, the decreased level and / or activity of BLM in cancer cells is the result of a frameshift mutation in the BLM gene. In some embodiments, the frameshift mutation in the BLM gene is a N515Mfs*16 frameshift deletion (e.g., a mutation in the BLM gene causing a N515Mfs*16 frameshift deletion relative to SEQ ID NO: 37). In some embodiments, the decreased level and / or activity of BLM in cancer cells is the result of a BLM gene loss in cancer cells. In some embodiments, the decreased level and / or activity of BLM in cancer cells is the result of one or more amino acid deletions in the protein encoded by the BLM gene. In some embodiments, the decreased level and / or activity of BLM in cancer cells is the result of one or more inactivating amino acid substitutions in the protein encoded by the BLM gene.

[0179] In some embodiments, the increase in cGAS / STING signaling pathway activity is a result of a decrease in the level and / or activity of PARP1 in cancer cells. In some embodiments, the decrease in the level and / or activity of PARP1 in cancer cells is a result of a frameshift mutation in the PARP1 gene. In some embodiments, the frameshift mutation in the PARP1 gene is a S507Afs*17 frameshift deletion (e.g., a mutation in the PARP1 gene causing a S507Afs*17 frameshift deletion relative to SEQ ID NO: 43). In some embodiments, the decrease in the level and / or activity of PARP1 in cancer cells is a result of PARP1 gene loss in cancer cells. In some embodiments, the decrease in the level and / or activity of PARP1 in cancer cells is a result of one or more amino acid deletions in the protein encoded by the PARP1 gene. In some embodiments, the decrease in the level and / or activity of PARP1 in cancer cells is a result of one or more inactivating amino acid substitutions in the protein encoded by the PARP1 gene.

[0180] In some embodiments, the increase in cGAS / STING signaling pathway activity is the result of a decrease in the level and / or activity of RPA1 in cancer cells. In some embodiments, the decrease in the level and / or activity of RPA1 in cancer cells is the result of a mutation that causes aberrant RPA1 mRNA splicing in cancer cells. In some embodiments, the mutation that causes aberrant RPA1 mRNA splicing in cancer cells is a X12 splice mutation. In some embodiments, the decrease in the level and / or activity of RPA1 in cancer cells is the result of RPA1 gene loss in cancer cells. In some embodiments, the decrease in the level and / or activity of RPA1 in cancer cells is the result of one or more amino acid deletions in the protein encoded by the RPA1 gene. In some embodiments, the decrease in the level and / or activity of RPA1 in cancer cells is the result of one or more inactivating amino acid substitutions in the protein encoded by the RPA1 gene.

[0181] In some embodiments, the increase in cGAS / STING signaling pathway activity is a result of a decrease in the level and / or activity of RAD51 in cancer cells. In some embodiments, the decrease in the level and / or activity of RAD51 in cancer cells is a result of one or more inactivating amino acid substitutions in the protein encoded by the RAD51 gene. In some embodiments, the one or more inactivating amino acid substitutions in the protein encoded by the RAD51 gene are R254* amino acid substitutions (e.g., a mutation in the RAD51 gene causing an R254* amino acid substitution to SEQ ID NO: 51). In some embodiments, the decrease in the level and / or activity of RAD51 in cancer cells is a result of RAD51 gene loss in cancer cells. In some embodiments, the decrease in the level and / or activity of RAD51 in cancer cells is a result of one or more amino acid deletions in the protein encoded by the RAD51 gene.

[0182] In some embodiments, the increased cGAS / STING signaling pathway activity is the result of increased levels and / or activity of MUS81 in the cancer cells. In some embodiments, the increased levels and / or activity of MUS81 in the cancer cells is the result of MUS81 gene amplification in the cancer cells. In some embodiments, the increased levels and / or activity of MUS81 in the cancer cells is the result of one or more activating amino acid substitutions in the protein encoded by the MUS81 gene.

[0183] In some embodiments, the increase in cGAS / STING signaling pathway activity is the result of an increase in the level and / or activity of IFI16 in cancer cells. In some embodiments, the increase in the level and / or activity of IFI16 in cancer cells is the result of IFI16 gene amplification in cancer cells. In some embodiments, the increase in the level and / or activity of IFI16 in cancer cells is the result of one or more activating amino acid substitutions in the protein encoded by the IFI16 gene.

[0184] In some embodiments, the increase in cGAS / STING signaling pathway activity is the result of an increase in the level and / or activity of cGAS in cancer cells. In some embodiments, the increase in the level and / or activity of cGAS in cancer cells is the result of cGAS gene amplification in cancer cells. In some embodiments, the increase in the level and / or activity of cGAS in cancer cells is the result of one or more activating amino acid substitutions in the protein encoded by the cGAS gene.

[0185] In some embodiments, the increased STING signaling pathway activity is the result of increased activity of STING in the cancer cell, hi some embodiments, the increased activity of STING in the cancer cell is the result of one or more activating amino acid substitutions in the protein encoded by the STING gene.

[0186] In some embodiments, the increase in cGAS / STING signaling pathway activity is the result of the increase in the level and / or activity of DDX41 in cancer cells.In some embodiments, the increase in the level and / or activity of DDX41 in cancer cells is the result of DDX41 gene amplification in cancer cells.In some embodiments, the increase in the level and / or activity of DDX41 in cancer cells is the result of one or more activating amino acid substitutions in the protein encoded by the DDX41 gene.

[0187] In some embodiments, the increased cGAS / STING signaling pathway activity is the result of increased levels and / or activity of EXO1 in the cancer cells. In some embodiments, the increased levels and / or activity of EXO1 in the cancer cells is the result of EXO1 gene amplification in the cancer cells. In some embodiments, the increased levels and / or activity of EXO1 in the cancer cells is the result of one or more activating amino acid substitutions in the protein encoded by the EXO1 gene.

[0188] In some embodiments, the increase in cGAS / STING signaling pathway activity is the result of an increase in the level and / or activity of DNA2 in the cancer cell. In some embodiments, the increase in the level and / or activity of DNA2 in the cancer cell is the result of DNA2 gene amplification in the cancer cell. In some embodiments, the increase in the level and / or activity of DNA2 in the cancer cell is the result of one or more activating amino acid substitutions in the protein encoded by the DNA2 gene.

[0189] In some embodiments, the increase in cGAS / STING signaling pathway activity is the result of an increase in the level and / or activity of RBBP8 (CtIP) in cancer cells. In some embodiments, the increase in the level and / or activity of RBBP8 (CtIP) in cancer cells is the result of RBBP8 (CtIP) gene amplification in cancer cells. In some embodiments, the increase in the level and / or activity of RBBP8 (CtIP) in cancer cells is the result of one or more activating amino acid substitutions in the protein encoded by the RBBP8 (CtIP) gene.

[0190] In some embodiments, the increased cGAS / STING signaling pathway activity is the result of increased levels and / or activity of MRE11 in the cancer cells. In some embodiments, the increased levels and / or activity of MRE11 in the cancer cells is the result of MRE11 gene amplification in the cancer cells. In some embodiments, the increased levels and / or activity of MRE11 in the cancer cells is the result of one or more activating amino acid substitutions in the protein encoded by the MRE11 gene.

[0191] In some embodiments, the subject has been diagnosed or identified as having cancer. In some embodiments, the cancer is selected from the group consisting of renal clear cell carcinoma, papillary renal cell carcinoma, chromophobe renal cell carcinoma, uveal melanoma, tongue squamous cell carcinoma, breast cancer, osteosarcoma, and skin cancer. In some embodiments, the cancer is selected from the group consisting of renal clear cell carcinoma, uveal melanoma, tongue squamous cell carcinoma, breast cancer, and skin cancer.

[0192] Further exemplary aspects that can be used or incorporated into these methods are described herein.

[0193] Methods for predicting subject responsiveness to STING antagonists The method of predicting the responsiveness of a subject (e.g., any exemplary subject described herein) to a STING antagonist comprises the steps of: (a) determining that the subject has cancer cells having one or both of: (i) a decrease in the level and / or activity of TREX1 (e.g., a decrease of about 1% to about 99%, or any subrange of this range described herein) (e.g., compared to a reference level); and (ii) an increase in cGAS / STING signaling pathway activity (e.g., an increase of 1% to 1000%, or any subrange of this range described herein) (e.g., compared to a reference level); or (II) an elevated level of cGAMP (e.g., an increase of 1% to 1000%, or any subrange of this range described herein) (e.g., compared to a reference level) in a serum sample or a tumor sample; and (b) determining that in step (a), (i) a decrease in the level and / or activity of TREX1 (e.g., a decrease of about 1% to about 99%, or any subrange of this range described herein) (e.g., compared to a reference level); and (ii) an increase in cGAS / STING signaling pathway activity (e.g., an increase of 1% to 1000%, or any subrange of this range described herein) (e.g., compared to a reference level). Provided herein are methods that include identifying a subject determined to have one or both of an increase in cGAS / STING signaling pathway activity (e.g., an increase of 1% to 1000%, or any subrange of this range as described herein) (e.g., compared to a reference level) or an elevated level of cGAMP (e.g., an increase of 1% to 1000%, or any subrange of this range as described herein) (e.g., compared to a reference level) in a serum sample or a tumor sample, as having an increased likelihood of responding to treatment with a STING antagonist, wherein the STING antagonist is a compound of any one of Formulas I-XXIV (e.g., Formulas XI-XV) or Formulas M1-M6 (e.g., Formulas M3-M6), or a compound set forth in Table C1.

[0194] 1. A method of predicting the responsiveness of a subject (e.g., any exemplary subject described herein) to a STING antagonist or cGAS inhibitor, comprising detecting (i) a decrease in the level and / or activity of TREX1 (e.g., a decrease of about 1% to about 99%, or any subrange of this range described herein) (e.g., compared to a reference level); and (ii) Also provided herein are methods that include identifying a subject determined to have cells (e.g., cancer cells) having one or both of increased cGAS / STING signaling pathway activity (e.g., an increase of 1% to 1000%, or any subrange of this range as described herein) (e.g., compared to a reference level) or an elevated level of cGAMP (e.g., an increase of 1% to 1000%, or any subrange of this range as described herein) (e.g., compared to a reference level) in a serum sample or a tumor sample, as having an increased likelihood of responding to treatment with a STING antagonist or cGAS inhibitor, wherein the STING antagonist is a compound of any one of Formulas I-XXIV (e.g., Formulas XI-XV) or Formulas M1-M6 (e.g., Formulas M3-M6), or a compound set forth in Table C1.

[0195] In some embodiments, the subject is identified as having cancer cells with a decreased level and / or activity of TREX1. In some embodiments, the subject is identified as having cancer cells with an increased cGAS / STING signaling pathway activity. In some embodiments, the subject is identified as having cancer cells with both (i) a decreased level and / or activity of TREX1 and (ii) an increased cGAS / STING signaling pathway activity (e.g., an increase of 1% to 1000%, or any subrange of this range described herein) (e.g., compared to a reference level), or the subject is identified as having an elevated level of cGAMP (e.g., an increase of 1% to 1000%, or any subrange of this range described herein) (e.g., compared to a reference level) in a serum sample or tumor sample. In some embodiments, the subject is identified as having cancer cells with a decreased level of TREX1. In some embodiments, the level of TREX1 is the level of TREX1 protein in the cancer cells. In some embodiments, identifying the subject as having cancer cells with a decreased level of TREX1 comprises detecting a decreased level of TREX1 protein in the cancer cells. In some embodiments, the level of TREX1 is the level of TREX1 mRNA in the cancer cells. In some embodiments, identifying a subject as having cancer cells with a decreased level of TREX1 comprises detecting a decreased level of TREX1 mRNA in the cancer cells.

[0196] In some embodiments, the reduced level and / or activity of TREX1 is a result of TREX1 gene loss in the cancer cells. In some embodiments, the TREX1 gene loss is a loss of one allele of the TREX1 gene. In some embodiments, the TREX1 gene loss is a loss of both alleles of the TREX1 gene. In some embodiments, identifying the subject as having cancer cells with reduced level and / or activity of TREX1 comprises detecting TREX1 gene loss in the cancer cells. In some embodiments, the reduced level and / or activity of TREX1 is a result of one or more amino acid deletions in a protein encoded by the TREX1 gene in the cancer cells. In some embodiments, identifying the subject as having cancer cells with reduced level and / or activity of TREX1 comprises detecting one or more amino acid deletions in a protein encoded by the TREX1 gene in the cancer cells. In some embodiments, the reduced level and / or activity of TREX1 is a result of one or more inactivating amino acid substitutions in a protein encoded by the TREX1 gene in the cancer cells. In some embodiments, identifying a subject as having cancer cells with reduced expression and / or activity of TREX1 comprises detecting one or more inactivating amino acid substitutions in a protein encoded by the TREX1 gene in the cancer cells.

[0197] In some embodiments, the increased cGAS / STING signaling pathway activity is a result of a decreased level and / or activity of BRCA1 in the cancer cell. In some embodiments, the decreased level and / or activity of BRCA1 in the cancer cell is a result of a frameshift mutation in the BRCA1 gene. In some embodiments, the frameshift mutation in the BRCA1 gene is an E111Gfs*3 frameshift insertion (e.g., a mutation in the BRCA1 gene causing an E111Gfs*3 frameshift insertion relative to SEQ ID NO: 15). In some embodiments, the decreased level and / or activity of BRCA1 in the cancer cell is a result of a BRCA1 gene loss in the cancer cell. In some embodiments, the decreased level and / or activity of BRCA1 in the cancer cell is a result of one or more amino acid deletions in the protein encoded by the BRCA1 gene. In some embodiments, the decreased level and / or activity of BRCA1 in the cancer cell is a result of one or more inactivating amino acid substitutions in the protein encoded by the BRCA1 gene.

[0198] In some embodiments, the increased cGAS / STING signaling pathway activity is a result of a decreased level and / or activity of the BRCA2 gene. In some embodiments, the decreased level and / or activity of BRCA2 in the cancer cell is a result of a frameshift mutation in the BRCA2 gene. In some embodiments, the frameshift mutation in the BRCA2 gene is a N1784Kfs*3 frameshift insertion (e.g., a mutation in the BRCA2 gene causing a N1784Kfs*3 frameshift insertion relative to SEQ ID NO: 25). In some embodiments, the decreased level and / or activity of BRCA2 in the cancer cell is a result of a BRCA2 gene loss in the cancer cell. In some embodiments, the decreased level and / or activity of BRCA2 in the cancer cell is a result of one or more amino acid deletions in the protein encoded by the BRCA2 gene. In some embodiments, the decreased level and / or activity of BRCA2 in the cancer cell is a result of one or more inactivating amino acid substitutions in the protein encoded by the BRCA2 gene.

[0199] In some embodiments, the increase in cGAS / STING signaling pathway activity is the result of a decrease in the level and / or activity of SAMHD1 in cancer cells. In some embodiments, the decrease in the level and / or activity of SAMHD1 in cancer cells is the result of one or more inactivating amino acid substitutions in the protein encoded by the SAMHD1 gene in cancer cells. In some embodiments, the one or more inactivating amino acid substitutions in the protein encoded by the SAMHD1 gene are V133I amino acid substitutions (e.g., a mutation in the SAMHD1 gene that causes a V133I amino acid substitution to SEQ ID NO: 27). In some embodiments, the decrease in the level and / or activity of SAMHD1 in cancer cells is the result of SAMHD1 gene loss in cancer cells. In some embodiments, the decrease in the level and / or activity of SAMHD1 in cancer cells is the result of one or more amino acid deletions in the protein encoded by the SAMHD1 gene.

[0200] In some embodiments, the increase in cGAS / STING signaling pathway activity is the result of a decrease in the level and / or activity of DNASE2 in cancer cells. In some embodiments, the decrease in the level and / or activity of DNASE2 in cancer cells is the result of one or more inactivating amino acid substitutions in the protein encoded by the DNASE2 gene in cancer cells. In some embodiments, the one or more inactivating amino acid substitutions in the protein encoded by the DNASE2 gene are R314W amino acid substitutions (e.g., a mutation in the DNASE2 gene that causes an R314W amino acid substitution to SEQ ID NO: 33). In some embodiments, the decrease in the level and / or activity of DNASE2 in cancer cells is the result of DNASE2 gene loss in cancer cells. In some embodiments, the decrease in the level and / or activity of DNASE2 in cancer cells is the result of one or more amino acid deletions in the protein encoded by the DNASE2 gene.

[0201] In some embodiments, the increased cGAS / STING signaling pathway activity is the result of a decreased level and / or activity of BLM in cancer cells. In some embodiments, the decreased level and / or activity of BLM in cancer cells is the result of a frameshift mutation in the BLM gene. In some embodiments, the frameshift mutation in the BLM gene is a N515Mfs*16 frameshift deletion (e.g., a mutation in the BLM gene causing a N515Mfs*16 frameshift deletion relative to SEQ ID NO: 37). In some embodiments, the decreased level and / or activity of BLM in cancer cells is the result of a BLM gene loss in cancer cells. In some embodiments, the decreased level and / or activity of BLM in cancer cells is the result of one or more amino acid deletions in the protein encoded by the BLM gene. In some embodiments, the decreased level and / or activity of BLM in cancer cells is the result of one or more inactivating amino acid substitutions in the protein encoded by the BLM gene.

[0202] In some embodiments, the increase in cGAS / STING signaling pathway activity is a result of a decrease in the level and / or activity of PARP1 in cancer cells. In some embodiments, the decrease in the level and / or activity of PARP1 in cancer cells is a result of a frameshift mutation in the PARP1 gene. In some embodiments, the frameshift mutation in the PARP1 gene is a S507Afs*17 frameshift deletion (e.g., a mutation in the PARP1 gene causing a S507Afs*17 frameshift deletion relative to SEQ ID NO: 43). In some embodiments, the decrease in the level and / or activity of PARP1 in cancer cells is a result of PARP1 gene loss in cancer cells. In some embodiments, the decrease in the level and / or activity of PARP1 in cancer cells is a result of one or more amino acid deletions in the protein encoded by the PARP1 gene. In some embodiments, the decrease in the level and / or activity of PARP1 in cancer cells is a result of one or more inactivating amino acid substitutions in the protein encoded by the PARP1 gene.

[0203] In some embodiments, the increase in cGAS / STING signaling pathway activity is the result of a decrease in the level and / or activity of RPA1 in cancer cells. In some embodiments, the decrease in the level and / or activity of RPA1 in cancer cells is the result of a mutation that causes aberrant RPA1 mRNA splicing in cancer cells. In some embodiments, the mutation that causes aberrant RPA1 mRNA splicing in cancer cells is a X12 splice mutation. In some embodiments, the decrease in the level and / or activity of RPA1 in cancer cells is the result of RPA1 gene loss in cancer cells. In some embodiments, the decrease in the level and / or activity of RPA1 in cancer cells is the result of one or more amino acid deletions in the protein encoded by the RPA1 gene. In some embodiments, the decrease in the level and / or activity of RPA1 in cancer cells is the result of one or more inactivating amino acid substitutions in the protein encoded by the RPA1 gene.

[0204] In some embodiments, the increase in cGAS / STING signaling pathway activity is a result of a decrease in the level and / or activity of RAD51 in cancer cells. In some embodiments, the decrease in the level and / or activity of RAD51 in cancer cells is a result of one or more inactivating amino acid substitutions in the protein encoded by the RAD51 gene. In some embodiments, the one or more inactivating amino acid substitutions in the protein encoded by the RAD51 gene are R254* amino acid substitutions (e.g., a mutation in the RAD51 gene causing an R254* amino acid substitution to SEQ ID NO: 51). In some embodiments, the decrease in the level and / or activity of RAD51 in cancer cells is a result of RAD51 gene loss in cancer cells. In some embodiments, the decrease in the level and / or activity of RAD51 in cancer cells is a result of one or more amino acid deletions in the protein encoded by the RAD51 gene.

[0205] In some embodiments, the increased cGAS / STING signaling pathway activity is the result of increased levels and / or activity of MUS81 in the cancer cells. In some embodiments, the increased levels and / or activity of MUS81 in the cancer cells is the result of MUS81 gene amplification in the cancer cells. In some embodiments, the increased levels and / or activity of MUS81 in the cancer cells is the result of one or more activating amino acid substitutions in the protein encoded by the MUS81 gene.

[0206] In some embodiments, the increase in cGAS / STING signaling pathway activity is the result of an increase in the level and / or activity of IFI16 in cancer cells. In some embodiments, the increase in the level and / or activity of IFI16 in cancer cells is the result of IFI16 gene amplification in cancer cells. In some embodiments, the increase in the level and / or activity of IFI16 in cancer cells is the result of one or more activating amino acid substitutions in the protein encoded by the IFI16 gene.

[0207] In some embodiments, the increase in cGAS / STING signaling pathway activity is the result of an increase in the level and / or activity of cGAS in cancer cells. In some embodiments, the increase in the level and / or activity of cGAS in cancer cells is the result of cGAS gene amplification in cancer cells. In some embodiments, the increase in the level and / or activity of cGAS in cancer cells is the result of one or more activating amino acid substitutions in the protein encoded by the cGAS gene.

[0208] In some embodiments, the increased STING signaling pathway activity is the result of increased activity of STING in the cancer cell, hi some embodiments, the increased activity of STING in the cancer cell is the result of one or more activating amino acid substitutions in the protein encoded by the STING gene.

[0209] In some embodiments, the increase in cGAS / STING signaling pathway activity is the result of the increase in the level and / or activity of DDX41 in cancer cells.In some embodiments, the increase in the level and / or activity of DDX41 in cancer cells is the result of DDX41 gene amplification in cancer cells.In some embodiments, the increase in the level and / or activity of DDX41 in cancer cells is the result of one or more activating amino acid substitutions in the protein encoded by the DDX41 gene.

[0210] In some embodiments, the increased cGAS / STING signaling pathway activity is the result of increased levels and / or activity of EXO1 in the cancer cells. In some embodiments, the increased levels and / or activity of EXO1 in the cancer cells is the result of EXO1 gene amplification in the cancer cells. In some embodiments, the increased levels and / or activity of EXO1 in the cancer cells is the result of one or more activating amino acid substitutions in the protein encoded by the EXO1 gene.

[0211] In some embodiments, the increase in cGAS / STING signaling pathway activity is the result of an increase in the level and / or activity of DNA2 in the cancer cell. In some embodiments, the increase in the level and / or activity of DNA2 in the cancer cell is the result of DNA2 gene amplification in the cancer cell. In some embodiments, the increase in the level and / or activity of DNA2 in the cancer cell is the result of one or more activating amino acid substitutions in the protein encoded by the DNA2 gene.

[0212] In some embodiments, the increase in cGAS / STING signaling pathway activity is the result of an increase in the level and / or activity of RBBP8 (CtIP) in cancer cells. In some embodiments, the increase in the level and / or activity of RBBP8 (CtIP) in cancer cells is the result of RBBP8 (CtIP) gene amplification in cancer cells. In some embodiments, the increase in the level and / or activity of RBBP8 (CtIP) in cancer cells is the result of one or more activating amino acid substitutions in the protein encoded by the RBBP8 (CtIP) gene.

[0213] In some embodiments, the increased cGAS / STING signaling pathway activity is the result of increased levels and / or activity of MRE11 in the cancer cells. In some embodiments, the increased levels and / or activity of MRE11 in the cancer cells is the result of MRE11 gene amplification in the cancer cells. In some embodiments, the increased levels and / or activity of MRE11 in the cancer cells is the result of one or more activating amino acid substitutions in the protein encoded by the MRE11 gene.

[0214] In some embodiments, the subject has been diagnosed or identified as having cancer. In some embodiments, the cancer is selected from the group consisting of renal clear cell carcinoma, papillary renal cell carcinoma, chromophobe renal cell carcinoma, uveal melanoma, tongue squamous cell carcinoma, breast cancer, osteosarcoma, and skin cancer. In some embodiments, the cancer is selected from the group consisting of renal clear cell carcinoma, uveal melanoma, tongue squamous cell carcinoma, breast cancer, and skin cancer.

[0215] In some embodiments, the methods further include administering a therapeutically effective amount of a STING antagonist to a subject identified as having an increased likelihood of responding to treatment with a STING antagonist.

[0216] Further exemplary aspects that can be used or incorporated into these methods are described herein.

[0217] Indications In some embodiments, methods are provided for treating a subject having a condition, disease, or disorder in which increased cGAS / STING signaling activity and / or decreased levels and / or activity of TREX1 contribute to the pathology and / or symptoms and / or progression of the condition, disease, or disorder, comprising administering to the subject an effective amount of a chemical entity described herein (e.g., a compound generally or specifically described herein or a pharma- ceutically acceptable salt thereof, or a composition comprising same). In some embodiments of any of the methods described herein, the subject may have, or may be identified or diagnosed as having, any condition, disease, or disorder in which increased cGAS / STING signaling activity and / or decreased levels and / or activity of TREX1 contribute to the pathology and / or symptoms and / or progression of the condition, disease, or disorder. In some embodiments of any of the methods described herein, the subject may be suspected of having, or may be exhibiting one or more symptoms of, any of the conditions, diseases, or disorders described herein.

[0218] In some embodiments, the condition, disease, or disorder is cancer (e.g., clear cell renal carcinoma, papillary renal cell carcinoma, chromophobe renal cell carcinoma, uveal melanoma, tongue squamous cell carcinoma, breast cancer, osteosarcoma, and skin cancer).

[0219] In some embodiments, the condition, disease, or disorder is cancer (eg, renal clear cell carcinoma, uveal melanoma, tongue squamous cell carcinoma, breast cancer, and skin cancer).

[0220] Combination therapy The present disclosure contemplates both monotherapy and combination therapy regimens.

[0221] In some embodiments, the methods described herein may further include administering one or more additional therapies (e.g., one or more additional therapeutic agents and / or one or more therapeutic regimens) in combination with the administration of the STING antagonist (e.g., any STING antagonist described herein).

[0222] In certain embodiments, the second therapeutic agent or treatment regimen is administered to the subject prior to contacting with or administering the STING antagonist (e.g., about 1 hour, or about 6 hours, or about 12 hours, or about 24 hours, or about 48 hours, or about 1 week, or about 1 month).

[0223] In other embodiments, the second therapeutic agent or treatment regimen is administered to the subject at about the same time as the STING antagonist is contacted or administered.For example, the second therapeutic agent or treatment regimen and the STING antagonist are administered to the subject at the same time in the same dosage form.As another example, the second therapeutic agent or treatment regimen and the STING antagonist are administered to the subject at the same time in separate dosage forms.

[0224] In yet other embodiments, the second therapeutic agent or treatment regimen is administered to the subject after contacting with or administering the STING antagonist (e.g., about 1 hour, or about 6 hours, or about 12 hours, or about 24 hours, or about 48 hours, or about 1 week, or about 1 month).

[0225] Patient Selection In some embodiments, the methods described herein include identifying a subject (e.g., patient) in need of treatment as having cells (e.g., cancer cells) having one or both of: (i) a decrease in the level and / or activity of TREX1; and (ii) an increase in cGAS / STING signaling pathway activity (e.g., an increase of 1% to 1000%, or any subrange of this range described herein) (e.g., compared to a reference level); or (II) an increase in the level of cGAMP (e.g., an increase of 1% to 1000%, or any subrange of this range described herein) (e.g., compared to a reference level) in a serum sample or a tumor sample. In some embodiments, the methods described herein include identifying a subject (e.g., patient) in need of treatment as having cells (e.g., cancer cells) having a decrease in the level and / or activity of TREX1. In some embodiments, the methods described herein include identifying a subject (e.g., patient) in need of treatment as having cells (e.g., cancer cells) having an increase in cGAS / STING signaling pathway activity. In some embodiments, the methods described herein include identifying a subject (e.g., a patient) in need of treatment as having cells (e.g., cancer cells) having both (i) a decreased level and / or activity of TREX1 and (ii) an increased cGAS / STING signaling pathway activity (e.g., an increase of 1% to 1000%, or any subrange of this range described herein) (e.g., compared to a reference level) or identifying a subject (e.g., a patient) in need of treatment as having an elevated level of cGAMP (e.g., an increase of 1% to 1000%, or any subrange of this range described herein) (e.g., compared to a reference level) in a serum sample or a tumor sample.

[0226] In some embodiments, the subject is identified as having a cell (e.g., a cancer cell) with a reduced level of TREX1. In some embodiments, identifying the subject as having a cell (e.g., a cancer cell) with a reduced level of TREX1 comprises detecting a reduced level of TREX1 protein in the cell. In some embodiments, the level of TREX1 is the level of TREX1 protein in the cell. In some embodiments, the level of TREX1 is the level of TREX1 mRNA in the cell. In some embodiments, identifying the subject as having a cell (e.g., a cancer cell) with a reduced level of TREX1 comprises detecting a reduced level of TREX1 mRNA in the cell. In some embodiments, the reduced level and / or activity of TREX1 is the result of gene loss in the cell. In some embodiments, the TREX1 gene loss is loss of one allele of the TREX1 gene. In some embodiments, the TREX1 gene loss is loss of both alleles of the TREX1 gene. In some embodiments, identifying the subject as having a cell (e.g., a cancer cell) with a reduced level and / or activity of TREX1 comprises detecting a TREX1 gene loss in the cell. In some embodiments, the decreased level and / or activity of TREX1 is the result of one or more amino acid deletions in the protein encoded by the TREX1 gene in the cell. In some embodiments, identifying a subject as having a cell (e.g., a cancer cell) with a decreased level and / or activity of TREX1 comprises detecting one or more amino acid deletions in the protein encoded by the TREX1 gene in the cell. In some embodiments, the decreased level and / or activity of TREX1 is the result of one or more inactivating amino acid substitutions in the protein encoded by the TREX1 gene in the cell. In some embodiments, identifying a subject as having a cancer cell with a decreased expression and / or activity of TREX1 comprises detecting one or more inactivating amino acid substitutions in the protein encoded by the TREX1 gene in the cell.

[0227] In some embodiments, the methods described herein involve treating a subject (e.g., a patient) in need of treatment with, for example, a BRCA1 protein having a gain of function mutation (e.g., a BRCA1 protein having an E111Gfs*3 frameshift insertion numbered according to SEQ ID NO: 15, a BRCA1 protein having an N1784Kfs*3 frameshift insertion numbered according to SEQ ID NO: 25, a SAMHD1 protein having a V133I amino acid substitution numbered according to SEQ ID NO: 27, a DNASE2 protein having a R314W amino acid substitution numbered according to SEQ ID NO: 33, a BLM protein having a N515Mfs*16 frameshift deletion numbered according to SEQ ID NO: 37, a PARP1 protein having a S507Afs*17 frameshift deletion numbered according to SEQ ID NO: 43, an RPA1 mRNA splicing mutation having a X12 splice mutation, or a mutation having a BRCA1 protein ... The method includes detecting a RAD51 protein having an R254* amino acid substitution, numbered according to 51, or a loss-of-function mutation (e.g., any of the exemplary loss-of-function mutations described herein), thereby identifying the cell (e.g., cancer cell) as having one or both of: (i) a decrease in TREX1 level and / or activity; and (ii) an increase in STING signaling pathway activity.

[0228] In some embodiments, the methods described herein include identifying a subject (e.g., a patient) in need of treatment as having cells (e.g., cancer cells) that have one or both of: (i) decreased levels and / or activity of TREX1 and (ii) increased cGAS / STING signaling pathway activity (e.g., using any of the exemplary methods described herein).

[0229] Methods for detecting the level of activity and / or expression of the cGAS / STING signaling pathway In some embodiments of any of the methods described herein, the cGAS / STING signaling pathway activity is secretion of type I IFN or type III IFN. In some embodiments of any of the methods described herein, the cGAS / STING signaling pathway activity is secretion of IFN-α. In some embodiments of any of the methods described herein, the cGAS / STING signaling pathway activity is secretion of IFN-β. Non-limiting examples of methods that can be used to detect the secretion of IFN-α and IFN-β include immunohistochemistry, immunoassays, such as enzyme-linked immunosorbent assay (ELISA), sandwich ELISA, immunoprecipitation, and immunofluorescence assay.

[0230] Non-limiting methods for detecting cGAMP in serum or tissue include immunoassays, such as enzyme-linked immunosorbent assays (ELISAs), sandwich ELISAs, immunoprecipitations, and immunofluorescence assays, as well as mass spectrometry.

[0231] In some embodiments of any of the methods described herein, the cGAS / STING signaling pathway activity can be the level and / or activity of an upstream activator in the cGAS / STING signaling pathway (e.g., the level of one or more (e.g., two, three, four, five, or six) of MUS81 mRNA, MUS81 protein, IFI16 mRNA, IFI16 protein, cGAS mRNA, cGAS protein, DDX41 mRNA, DDX41 protein, EXO1 mRNA, EXO1 protein, DNA2 mRNA, DNA2 protein, RBBP8 mRNA, RBBP8 protein, MRE11 mRNA, or MRE11 protein in a mammalian cell (e.g., a mammalian cell obtained from a subject). In some embodiments of any of the methods described herein, cGAS / STING signaling pathway activity can be determined by detecting the level and / or activity of an upstream repressor of the cGAS / STING signaling pathway (e.g., the level of one or more (e.g., two, three, four, five, or six) of BRCA1 mRNA, BRCA1 protein, BRCA2 mRNA, BRCA2 protein, SAMHD1 mRNA, SAMHD1 protein, DNASE2 mRNA, DNASE2 protein, BLM mRNA, BLM protein, PARP1 mRNA, PARP1 protein, RPA1 mRNA, RPA1 protein, RAD51 mRNA, or RAD51 protein in a mammalian cell (e.g., a mammalian cell obtained from a subject).

[0232] Non-limiting assays that can be used to determine the level and / or activity of upstream activators or repressors of the STING pathway include Southern blot analysis, Northern blot analysis, polymerase chain reaction (PCR)-based methods such as next-generation sequencing, reverse transcription polymerase chain reaction (RT-PCR), TaqMan™, microarray analysis, immunohistochemistry, immunoassays such as enzyme-linked immunosorbent assay (ELISA), sandwich ELISA, immunoprecipitation, immunofluorescence assays, mass spectrometry, immunoblotting (Western blot), RIA, and flow cytometry.

[0233] In some embodiments of any of the methods described herein, the mammalian cell having an increased level of cGAS / STING signaling pathway activity has one or more of the following mammalian gain-of-function mutations in a cGAS / STING signaling pathway gene (e.g., a BRCA1 protein having an E111Gfs*3 frameshift insertion numbered according to SEQ ID NO: 15, a BRCA1 protein having an N1784Kfs*3 frameshift insertion numbered according to SEQ ID NO: 25, a SAMHD1 protein having a V133I amino acid substitution numbered according to SEQ ID NO: 27, a DNASE2 protein having a R314W amino acid substitution numbered according to SEQ ID NO: 33, a BLM protein having a N515Mfs*16 frameshift deletion numbered according to SEQ ID NO: 37, a PARP1 protein having a S507Afs*17 frameshift deletion numbered according to SEQ ID NO: 43, an RPA1 mRNA splicing with a X12 splice mutation, or a BRCA1 protein having an N1784Kfs*3 frameshift insertion numbered according to SEQ ID NO: 44, a BRCA1 protein having an N1784Kfs*3 frameshift insertion numbered according to SEQ ID NO: 45, a BRCA1 protein having an N1784Kfs*3 frameshift insertion numbered according to SEQ ID NO: 46, a BRCA1 protein having an N1784Kfs*3 frameshift insertion numbered according to SEQ ID NO: 47, a BRCA1 protein having an N1784Kfs*3 frameshift insertion numbered according to SEQ ID NO: 48, a BRCA1 protein having an N1784Kfs*3 frameshift insertion numbered according to SEQ ID NO: 49, a BRCA1 protein having an N1784Kfs*3 frameshift insertion numbered according to SEQ ID NO: The gene can be identified by detecting the presence of a RAD51 protein having an R254* amino acid substitution (numbered according to 51).

[0234] In some embodiments of any of the methods described herein, mammalian cells having reduced levels and / or activity of TREX1 can be identified, for example, by detecting the presence of a loss-of-function mutation in the TREX1 gene (e.g., TREX1 gene loss (e.g., loss of TREX1 in one or both alleles), an amino acid deletion in the protein encoded by the TREX1 gene, or an inactivating amino acid substitution in the protein encoded by the TREX1 gene). Non-limiting examples of assays that can be used to determine the level of presence of any of these mutations (e.g., any of the mutations described herein) include Southern blot analysis, Northern blot analysis, mass spectrometry, UV absorbance, lab-on-a-chip, microfluidics, gene chips, intercalating dyes (e.g., ethidium bromide), gel electrophoresis, restriction digestion and electrophoresis, and sequencing, including polymerase chain reaction (PCR)-based methods (e.g., using any of the wide variety of sequencing methods described herein or known in the art), such as next-generation sequencing, reverse transcription polymerase chain reaction (RT-PCR), TaqMan™, and microarray analysis.

[0235] For example, detection of genomic DNA can include detection of the presence of one or more unique sequences found in genomic DNA (e.g., human genomic DNA) (e.g., satellite DNA sequences present in centromeres or heterochromatin, minisatellite sequences, microsatellite sequences, sequences of transposable elements, telomeric sequences, specific sequences (e.g., 250 base pairs to about 300 base pairs) containing one or more SNPs, or specific sequences encoding genes). Detection can be performed using labeled probes (e.g., fluorophore-labeled probes, radioisotope-labeled probes, enzyme-labeled probes, quencher-labeled probes, and enzyme-labeled probes), for example, by hybridizing the labeled probe to genomic DNA present in the isolated genomic DNA sample or control sample (e.g., in an electrophoretic gel), or to the products of a PCR assay (e.g., a real-time PCR assay), or to the products of an assay that includes a PCR assay that utilizes genomic DNA in the isolated genomic DNA authentication sample or control sample as a template. Non-limiting examples of methods that can be used to generate probes include nick translation, random oligo-primed synthesis, and end-labeling.

[0236] Various assays for determining the genotype of a gene are known in the art. Non-limiting examples of these assays (which may be used in any of the methods described herein) include dynamic allele-specific hybridization (see, e.g., Howell et al., Nature Biotechnol. 17:87-88, 1999), molecular beacon assays (see, e.g., Marras et al., "Genotyping Single Nucleotide Polymorphisms with Molecular Beacons," In Kwok (Ed.), Single Nucleotide Polymorphisms: Methods and Protocols, Humana Press, Inc., Totowa, NJ, Vol. 212, pp. 111-128, 2003), microarrays (see, e.g., Affymetrix Human SNP 5.0 GeneChip), restriction fragment length polymorphism (RFLP) (see, e.g., Ota et al., Nature Protocols 2:2857-2864, 2007), PCR-based assays (see, e.g., tetra-primer ARMS-PCR (see, e.g., Zhang et al., Plos One 8:e62126, 2013), real-time PCR, allele-specific PCR (see, e.g., Gaudet et al., Methods Mol. Biol. 578:415-424, 2009), as well as TaqMan assay SNP genotyping (see, e.g., Woodward, Methods Mol. Biol. 1145:67-74, 2014 and Life Technologies' TaqMan® OpenArray® genotyping plates), flap endonuclease assay (also called Invader assay) (see, e.g., Olivier et al., Mutat. Res. 573:103-110, 2005), oligonucleotide ligation assay (see, e.g., Bruce et al., Biotechniques 45:559-571, 2008), single-stranded conformation polymorphism assay (see, e.g., Tahira et al., Human Mutat. 26:69-77, 2005), temperature gradient gel electrophoresis (see, e.g., Jones et al., "Temporal Temperature Gradient Electrophoresis for Detection of Single Nucleotide Polymorphisms," in Single Nucleotide Polymophisms: Methods and Protocols, Volume 578, pp. 153-165, 2008) or temperature gradient capillary electrophoresis, denaturing high performance liquid chromatography (see, e.g., Yu et al., J. Clin. Pathol. 58:479-485, 2005), high resolution melting of amplified sequences containing SNPs (see, e.g., Wittwer et al., Clinical Chemistry 49:853-860, 2003), or sequencing (e.g., Maxam-Gilbert sequencing, chain termination, shotgun sequencing, bridge PCR, as well as next-generation sequencing methods (e.g., massively parallel signature sequencing, polony sequencing, 454 pyrosequencing, Illumina (Solexa) sequencing, SOLiD sequencing, Ion Torrent semiconductor sequencing, DNA nanoball sequencing, HeliScope single molecule sequencing, and single molecule real-time sequencing). Further details and an overview of various next-generation sequencing methods are provided in Koboldt et al., Cell 155:27-38, 2013.

[0237] In some embodiments of any of the methods described herein, genotyping of the genes comprises a PCR assay (e.g., a real-time PCR assay) (with or without a prior preamplification step (e.g., any of the preamplification methods described herein)). In some embodiments of any of the methods described herein, genotyping can be performed using TaqMan®-based sequencing (e.g., TaqMan®-based OpenArray® sequencing, e.g., high-throughput TaqMan®-based OpenArray® sequencing) (with or without a prior preamplification step (e.g., any of the preamplification methods described herein)).

[0238] In some embodiments of any of the methods described herein, protein or mRNA levels can be detected in biological samples including blood, serum, exosomes, plasma, tissue, urine, feces, sputum, and cerebrospinal fluid.

[0239] In some embodiments of any of the methods described herein, the level of at least one (e.g., two, three, four, five, six, seven, or eight) parameters associated with activity and / or expression of the cGAS / STING signaling pathway, e.g., in any combination, may be determined.

[0240] In one aspect, the cells can be cells isolated from a subject being screened for the presence of cancer or an indication associated with increased cGAS / STING signaling pathway activity and / or decreased levels or activity of TREX1.

[0241] Reference Level In some embodiments of any of the methods described herein, the reference level may be a corresponding level detected in a similar cell or sample obtained from a healthy subject (e.g., a subject who has not been diagnosed or identified as having cancer, or any disorder associated with increased cGAS / STING signaling pathway activity and / or decreased level and / or activity of TREX1) (e.g., a subject who is not suspected of or at increased risk of developing cancer, or any disorder associated with increased cGAS / STING signaling pathway activity and / or decreased level and / or activity and / or expression of TREX1) (e.g., a subject who does not exhibit any symptoms of cancer, or any disorder associated with increased cGAS / STING signaling pathway activity and / or decreased level and / or activity of TREX1).

[0242] In some embodiments, the reference level may be a percentile value (e.g., mean, 99% percentile, 95% percentile, 90% percentile, 85% percentile, 80% percentile, 75% percentile, 70% percentile, 65% percentile, 60% percentile, 55% percentile, or 50% percentile) relative to a corresponding level detected in a similar sample in a population of healthy subjects (e.g., a population of subjects that have not been diagnosed or identified as having cancer, or any disorder associated with increased cGAS / STING signaling pathway activity and / or decreased level and / or activity of TREX1) (e.g., a population of subjects that are not suspected of developing or are not at increased risk of developing cancer, or any disorder associated with increased cGAS / STING signaling pathway activity and / or decreased level and / or activity of TREX1) (e.g., a population of subjects that do not exhibit any symptoms of cancer, or any disorder associated with increased cGAS / STING signaling pathway activity and / or decreased level and / or activity of TREX1).

[0243] In some embodiments, the reference value can be a corresponding level detected in a similar sample obtained from the subject at an earlier time point.

[0244] STING antagonists In any of the methods described herein, the STING antagonist can be any STING antagonist described herein (e.g., any compound described in this section). In any of the methods described herein, the STING antagonist has an IC for STING of about 1 nM to about 10 μM. 50 has.

[0245] In some embodiments, the STING antagonist is a compound of formula (I), or a pharma- ceutically acceptable salt or N-oxide thereof: TIFF2024502755000004.tif46128 formula, Z, Y 1 , Y 2 , Y 3 , Y 4 , X 1 , X 2 , W, Q, and A may be as defined anywhere in International Publication No. PCT / US2019 / 040317, filed July 2, 2019; U.S. Provisional Application No. 62 / 693,768, filed July 3, 2018; and U.S. Provisional Application No. 62 / 861,825, filed June 14, 2019, each of which is incorporated by reference in its entirety.

[0246] In some of these embodiments, Z, Y 1 , Y 2 , Y 3 , Y 4 , X 1 , X 2 , W, Q, and A are each as defined in any one of claims 1 to 255 of International Publication No. PCT / US2019 / 040317, filed on July 2, 2019, which is incorporated by reference in its entirety.

[0247] In certain embodiments, the STING antagonist is a compound described in the table covering pages 93-158 of International Publication No. 2020 / 010092, filed as PCT / US2019 / 040317 on July 2, 2019, which is incorporated by reference in its entirety into this specification.

[0248] In some embodiments, the STING antagonist is a compound of formula (II) or a pharma- ceutically acceptable salt thereof: TIFF2024502755000005.tif30128 formula, Y 1 , Y 2 , X, Z, W, Q, and A may be as defined anywhere in International Publication No. PCT / US2019 / 040418, filed July 2, 2019; U.S. Provisional Application No. 62 / 693,878, filed July 3, 2018; and U.S. Provisional Application No. 62 / 861,078, filed June 13, 2019, each of which is incorporated by reference in its entirety.

[0249] In some of these embodiments, Y 1 , Y 2 , X, Z, W, Q, and A are each as defined in any one of claims 1 to 115 of International Publication No. PCT / US2019 / 040418, filed on July 2, 2019, which is incorporated by reference in its entirety.

[0250] In certain embodiments, the STING antagonist is a compound described in the table on pages 34-44 of International Publication No. WO 2020 / 010155, filed as PCT / US2019 / 040418 on July 2, 2019, which is incorporated by reference in its entirety into this specification.

[0251] In some embodiments, the STING antagonist is a compound of formula (III), or a pharma- ceutically acceptable salt or tautomer thereof: TIFF2024502755000006.tif19128 formula, A, W 1 , W 2 A, B, and C may be as defined anywhere in International Publication No. 2020 / 150417, filed as PCT / US2020 / 013786, on January 16, 2020; U.S. Provisional Application No. 62 / 793,795, filed January 17, 2019; U.S. Provisional Application No. 62 / 861,865, filed June 14, 2019; U.S. Provisional Application No. 62 / 869,914, filed July 2, 2019; and U.S. Provisional Application No. 62 / 955,891, filed December 31, 2019, each of which is incorporated by reference in its entirety.

[0252] In some of these embodiments, A, W 1 , W 2 and B are each as defined in any one of claims 1 to 116 of International Publication No. WO 2020 / 150417, filed as PCT / US2020 / 013786 on January 16, 2020, which is incorporated herein by reference in its entirety.

[0253] In some embodiments, the STING antagonist is a compound of formula (IV), or a pharma- ceutically acceptable salt or tautomer thereof: TIFF2024502755000007.tif39128 formula, Z, Y 1 , Y 2 , Y 3 , R 6 , B, R 2N , L 3 , and R 4 may be as defined anywhere in International Publication No. 2020 / 150417, filed as PCT / US2020 / 013786, on January 16, 2020; U.S. Provisional Application No. 62 / 793,795, filed January 17, 2019; U.S. Provisional Application No. 62 / 861,865, filed June 14, 2019; U.S. Provisional Application No. 62 / 869,914, filed July 2, 2019; and U.S. Provisional Application No. 62 / 955,891, filed December 31, 2019, each of which is incorporated by reference in its entirety.

[0254] In some of these embodiments, Z, Y 1 , Y 2 , Y 3 , R 6 , B, R 2N , L 3 , and R 4 are as defined in any one of claims 117 to 223 of International Publication No. 2020 / 150417, filed as PCT / US2020 / 013786 on January 16, 2020, each of which is incorporated herein by reference in its entirety.

[0255] In certain embodiments, the STING antagonist is a compound described in Table C1 of International Publication No. WO 2020 / 150417, filed as PCT / US2020 / 013786 on January 16, 2020, which is incorporated by reference in its entirety.

[0256] In some embodiments, the STING antagonist is a compound of formula (V), or a pharma- ceutically acceptable salt or tautomer thereof: TIFF2024502755000008.tif40128 formula, X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 , Z, Q, A, and R 6 may be as defined anywhere in International Publication No. WO 2020 / 236586, filed as PCT / US2020 / 033127, on May 15, 2020; U.S. Provisional Application No. 62 / 849,811, filed May 17, 2019; and U.S. Provisional Application No. 62 / 861,880, filed June 14, 2019, each of which is incorporated by reference in its entirety.

[0257] In some of these embodiments, X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4, Z, Q, A, and R 6 are as defined in any one of claims 1 to 18 and any one of item numbers 1 to 271 of International Publication No. 2020 / 236586, filed as PCT / US2020 / 033127 on May 15, 2020, each of which is incorporated herein by reference in its entirety.

[0258] In certain embodiments, the STING antagonist is a compound described in Table C1 of International Publication No. WO 2020 / 236586, filed as PCT / US2020 / 033127 on May 15, 2020, which is incorporated by reference in its entirety.

[0259] In some embodiments, the STING antagonist is a compound of formula (VI), or a pharma- ceutically acceptable salt or tautomer thereof: TIFF2024502755000009.tif28128 formula, X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 , Z, W, and R 6 may be as defined anywhere in International Publication No. 2020 / 243519, filed as PCT / US2020 / 035249 on May 29, 2020; U.S. Provisional Application No. 62 / 854,288, filed May 29, 2019, which are incorporated by reference in their entireties.

[0260] In some of these embodiments, X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 , Z, W, and R 6are as defined in any one of claims 1-16 and any one of item numbers 1-223 and 279-287 of International Publication No. 2020 / 243519, filed as PCT / US2020 / 035249 on May 29, 2020, each of which is incorporated by reference in its entirety.

[0261] In certain embodiments, the STING antagonist is a compound described in Table C1 of International Publication No. WO 2020 / 243519, filed as PCT / US2020 / 035249 on May 29, 2020, which is incorporated by reference in its entirety.

[0262] In some embodiments, the STING antagonist is a compound of formula (VII), or a pharma- ceutically acceptable salt or tautomer thereof: TIFF2024502755000010.tif27128 formula, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , R 6 , W, and A may be as defined anywhere in International Publication No. 2020 / 252240, filed as PCT / US2020 / 037403, on June 12, 2020; U.S. Provisional Application No. 62 / 861,714, filed June 14, 2019; and U.S. Provisional Application No. 62 / 955,924, filed December 31, 2019, each of which is incorporated by reference in its entirety.

[0263] In some of these embodiments, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , R 6 , W, and A are as defined in any one of claims 1-16 and any one of item numbers 1-328 of PCT / US2020 / 037403, filed June 12, 2020, which is incorporated by reference in its entirety herein.

[0264] In certain embodiments, the STING antagonist is a compound described in Table C1 of PCT / US2020 / 037403, filed June 12, 2020, which is incorporated by reference in its entirety.

[0265] In some embodiments, the STING antagonist is a compound of formula (VIII) or a pharma- ceutically acceptable salt thereof: TIFF2024502755000011.tif28128 formula, R 1 , R 2 , R 3 , R 4 , R 5 , W, Q, and A may be as defined anywhere in International Publication No. 2020 / 106741, filed as PCT / US2019 / 062245, on November 19, 2019; U.S. Provisional Application No. 62 / 769,500, filed November 19, 2018; and U.S. Provisional Application No. 62 / 861,108, filed June 13, 2019, each of which is incorporated by reference in its entirety.

[0266] In some of these embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , W, Q, and A are each as defined in any one of claims 1 to 118 of International Publication No. PCT / US2019 / 062245, filed on November 19, 2019, which is incorporated by reference in its entirety.

[0267] In certain embodiments, the STING antagonist is a compound described in the tables on pages 56-69 of International Publication No. 2020 / 106741, filed as PCT / US2019 / 062245 on November 19, 2019, each of which is incorporated by reference in its entirety into this specification.

[0268] In some embodiments, the STING antagonist is a compound of formula (IX), or a pharma- ceutically acceptable salt or tautomer thereof: TIFF2024502755000012.tif23128 formula, A, B, W, and R N may be as defined anywhere in International Publication No. 2020 / 106736, filed as PCT / US2019 / 062238, on November 19, 2019; U.S. Provisional Application No. 62 / 769,327, filed November 19, 2018; and U.S. Provisional Application No. 62 / 861,781, filed June 14, 2019, each of which is incorporated by reference in its entirety.

[0269] In some of these embodiments, A, B, W, and R N are as defined in any one of claims 1 to 298 of International Publication No. 2020 / 106736, filed as PCT / US2019 / 062238 on November 19, 2019, each of which is incorporated herein by reference in its entirety.

[0270] In certain embodiments, the STING antagonist is a compound described in Tables 1A and 1B of International Publication No. 2020 / 106736, filed as PCT / US2019 / 062238 on November 19, 2019, each of which is incorporated by reference in its entirety into this specification.

[0271] In some embodiments, the STING antagonist is a compound of formula (X), or a pharma- ceutically acceptable salt or tautomer thereof: TIFF2024502755000013.tif15128 formula, A, B, and L ABmay be as defined anywhere in International Publication No. 2020 / 150439, filed as PCT / US2020 / 013824, on January 16, 2020; U.S. Provisional Application No. 62 / 793,623, filed January 17, 2019; and U.S. Provisional Application No. 62 / 861,702, filed June 14, 2019, each of which is incorporated by reference in its entirety.

[0272] In some of these embodiments, A, B, and L AB are as defined in any one of claims 1-116 and 172-249 of International Publication No. 2020 / 150439, filed as PCT / US2020 / 013824 on January 16, 2020, each of which is incorporated by reference in its entirety.

[0273] In certain embodiments, the STING antagonist is a compound described in Table C1 of International Publication No. WO 2020 / 150439, filed as PCT / US2020 / 013824 on January 16, 2020, each of which is incorporated by reference in its entirety herein.

[0274] In some embodiments, the STING antagonist is a compound of formula (XI) or a pharma- ceutically acceptable salt or tautomer thereof: TIFF2024502755000014.tif37128 formula, X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 , Z, Q, A, and R 6 may be as defined anywhere in International Publication No. 2021 / 067791, filed as PCT / US2020 / 054054, on October 2, 2020; U.S. Provisional Application No. 62 / 910,162, filed October 3, 2019; and U.S. Provisional Application No. 62 / 955,921, filed December 31, 2019, each of which is incorporated by reference in its entirety.

[0275] In some of these embodiments, X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 , Z, Q, A, and R 6 are as defined in any one of claims 1-16 and any one of item numbers 1-179 of PCT / US2020 / 054054, filed October 2, 2020, each of which is incorporated herein by reference in its entirety.

[0276] In certain embodiments, the STING antagonist is a compound described in Table C1 of PCT / US2020 / 054054, filed October 2, 2020, each of which is incorporated by reference in its entirety into this specification.

[0277] In some embodiments, the STING antagonist is a compound of formula (XII), or a pharma- ceutically acceptable salt or tautomer thereof: TIFF2024502755000015.tif42128 formula, R 1a , R 1b , R 1c , R 1d , X 1 , X 2 , Q, A, and R 6 may be as defined anywhere in International Publication No. 2021 / 067805, filed as PCT / US2020 / 054069, on October 2, 2020; U.S. Provisional Application No. 62 / 910,160, filed October 3, 2019; and U.S. Provisional Application No. 62 / 955,867, filed December 31, 2019, each of which is incorporated by reference in its entirety.

[0278] In some of these embodiments, R 1a , R 1b , R 1c , R 1d , X 1 , X 2 , Q, A, and R 6are as defined in any one of claims 1 to 16 and any one of item numbers 1 to 296 of PCT / US2020 / 054069, filed October 2, 2020, each of which is incorporated by reference in its entirety herein.

[0279] In certain embodiments, the STING antagonist is a compound set forth in Table C1 of PCT / US2020 / 054069, filed October 2, 2020, each of which is incorporated by reference in its entirety herein.

[0280] In some embodiments, the STING antagonist is a compound of formula (XIII), or a pharma- ceutically acceptable salt or tautomer thereof: TIFF2024502755000016.tif34128 formula, R 1a , R 1b , R 1c , R 1d , X 1 , X 2 , W, Q, A, and R 6 may be as defined anywhere in International Publication No. 2021 / 067801, filed as PCT / US2020 / 054064, on October 2, 2020; U.S. Provisional Application No. 62 / 910,230, filed October 3, 2019; and U.S. Provisional Application No. 62 / 955,899, filed December 31, 2019, each of which is incorporated by reference in its entirety.

[0281] In some of these embodiments, R 1a , R 1b , R 1c , R 1d , X 1 , X 2 , W, Q, A, and R 6 are as defined in any one of claims 1 to 16 and any one of item numbers 1 to 181 of PCT / US2020 / 054064, filed October 2, 2020, each of which is incorporated by reference in its entirety herein.

[0282] In certain embodiments, the STING antagonist is a compound described in Table C1 of PCT / US2020 / 054064, filed October 2, 2020, each of which is incorporated by reference in its entirety into this specification.

[0283] In some embodiments, the STING antagonist is a compound of formula (XIV), or a pharma- ceutically acceptable salt or tautomer thereof: TIFF2024502755000017.tif32128 formula, Z, Y 1 , Y 2 , Y 3 , X 1 , X 2 , R 6 , W, Q, P 1 , P 2 , P 3 , P 4 , and P 5 may be as defined anywhere in International Publication No. 2021 / 138419, filed as PCT / US2020 / 067463, on December 30, 2020; U.S. Provisional Application No. 63 / 090,547, filed October 12, 2020; and U.S. Provisional Application No. 62 / 955,853, filed December 31, 2019, each of which is incorporated by reference in its entirety.

[0284] In some of these embodiments, Z, Y 1 , Y 2 , Y 3 , X 1 , X 2 , R 6 , W, Q, P 1 , P 2 , P 3 , P 4 , and P 5 are as defined in any one of claims 1-16 and any one of item numbers 1-220 of U.S. Provisional Application No. 63 / 090,547, filed October 12, 2020, each of which is incorporated by reference in its entirety herein.

[0285] In certain embodiments, the STING antagonist is a compound set forth in Table C1 of U.S. Provisional Application No. 63 / 090,547, filed October 12, 2020, each of which is incorporated by reference in its entirety herein.

[0286] In some embodiments, the STING antagonist is a compound of formula (XV), or a pharma- ceutically acceptable salt or tautomer thereof: TIFF2024502755000018.tif38128 formula, R 1a , R 1b , R 1c , R 1d , X 1 , X 2 , R 6 , W, Q, P 1 , P 2 , P 3 , P 4 , and P 5 may be as defined anywhere in International Publication No. 2021 / 138434, filed as PCT / US2020 / 067483, on December 30, 2020; U.S. Provisional Application No. 63 / 090,538, filed October 12, 2020; and U.S. Provisional Application No. 62 / 955,839, filed December 31, 2019, each of which is incorporated by reference in its entirety.

[0287] In some of these embodiments, R 1a , R 1b , R 1c , R 1d , X 1 , X 2 , R 6 , W, Q, P 1 , P 2 , P 3 , P 4 , and P 5 are as defined in any one of claims 1-16 and any one of item numbers 1-240 of U.S. Provisional Application No. 63 / 090,538, filed October 12, 2020, each of which is incorporated by reference in its entirety herein.

[0288] In certain embodiments, the STING antagonist is a compound set forth in Table C1 of U.S. Provisional Application No. 63 / 090,538, filed October 12, 2020, each of which is incorporated by reference in its entirety herein.

[0289] In some embodiments, the STING antagonist is a compound of formula (XVI), or a pharma- ceutically acceptable salt or tautomer thereof: TIFF2024502755000019.tif27128 formula, Q 2 , L A , a1, Q 1 Tamaki, Y. 1 , Y 2 , Y 3 , X 1 , X 2 , R 6 , and W may be as defined anywhere in PCT / US2021 / 041823, filed July 15, 2021; and U.S. Provisional Application No. 63 / 052,084, filed July 15, 2020, each of which is incorporated by reference in its entirety.

[0290] In some of these aspects, Q 2 , L A , a1, Q 1 Tamaki, Y. 1 , Y 2 , Y 3 , X 1 , X 2 , R 6 , and W are as defined in any one of claims 1-20 and any one of item numbers 1-176 of PCT / US2021 / 041823, filed July 15, 2021, which are incorporated by reference in their entireties.

[0291] In certain embodiments, the STING antagonist is a compound described in Table C1 of PCT / US2021 / 041823, filed July 15, 2021, each of which is incorporated by reference in its entirety into this specification.

[0292] In some embodiments, the STING antagonist is a compound of formula (XVII), or a pharma- ceutically acceptable salt or tautomer thereof: TIFF2024502755000020.tif27128 formula, Z, Y 1 , Y 2 , Y 3 , X 1 , X 2 , R 6 , P 1 , P 2 , P 3 , P 4 , and P 5 may be as defined anywhere in PCT / US2021 / 041820, filed July 15, 2021; and U.S. Provisional Application No. 63 / 052,086, filed July 15, 2020, each of which is incorporated by reference in its entirety.

[0293] In some of these embodiments, Z, Y 1 , Y 2 , Y 3 , X 1 , X 2 , R 6 , P 1 , P 2 , P 3 , P 4 , and P 5 are as defined in any one of claims 1 to 19 and any one of item numbers 1 to 193 of PCT / US2021 / 041820, filed July 15, 2021, each of which is incorporated by reference in its entirety into this specification.

[0294] In certain embodiments, the STING antagonist is a compound described in Table C1 of PCT / US2021 / 041820, filed July 15, 2021, each of which is incorporated by reference in its entirety into this specification.

[0295] In some embodiments, the STING antagonist is a compound of formula (XVIII), or a pharma- ceutically acceptable salt or tautomer thereof: TIFF2024502755000021.tif28128 formula, Z, Y 1 , Y 2 , Y 3 , X 1 , X 2 , R 6 , B ring, L A , a1, and the C ring may be as defined anywhere in PCT / US2021 / 041817, filed July 15, 2021; and U.S. Provisional Application No. 63 / 052,080, filed July 15, 2020, each of which is incorporated by reference in its entirety.

[0296] In some of these embodiments, Z, Y 1 , Y 2 , Y 3 , X 1 , X 2 , R 6 , B ring, L A , a1, and the C ring are as defined in any one of claims 1 to 20 and any one of item numbers 1 to 196 of PCT / US2021 / 041817, filed July 15, 2021, each of which is incorporated by reference in its entirety.

[0297] In certain embodiments, the STING antagonist is a compound described in Table C1 of PCT / US2021 / 041817, filed July 15, 2021, each of which is incorporated by reference in its entirety into this specification.

[0298] In some embodiments, the STING antagonist is a compound of formula (XIX), or a pharma- ceutically acceptable salt or tautomer thereof: TIFF2024502755000022.tif28128 formula, Z, Y 1 , Y 2 , Y 3 , X 1 , X 2 , R 6 , B ring, L A , a1, C ring, and R 7may be as defined anywhere in PCT / US2021 / 041792, filed July 15, 2021; and U.S. Provisional Application No. 63 / 052,117, filed July 15, 2020, each of which is incorporated by reference in its entirety.

[0299] In some of these embodiments, Z, Y 1 , Y 2 , Y 3 , X 1 , X 2 , R 6 , B ring, L A , a1, C ring, and R 7 are as defined in any one of claims 1 to 17 and any one of item numbers 1 to 173 of PCT / US2021 / 041792, filed July 15, 2021, each of which is incorporated by reference in its entirety into this specification.

[0300] In certain embodiments, the STING antagonist is a compound described in Table C1 of PCT / US2021 / 041792, filed July 15, 2021, each of which is incorporated by reference in its entirety into this specification.

[0301] In some embodiments, the STING antagonist is a compound of formula (XX), or a pharma- ceutically acceptable salt or tautomer thereof: TIFF2024502755000023.tif26128 formula, Q 2 , L A , a1, Q 1 , Y 1 , Y 2 , Y 3 , X 1 , X 2 , R 6 , and W may be as defined anywhere in U.S. Utility Application No. 17 / 376,823, filed July 15, 2021; and U.S. Provisional Application No. 63 / 052,076, filed July 15, 2020, each of which is incorporated by reference in its entirety.

[0302] In some of these aspects, Q2 , L A , a1, Q 1 , Y 1 , Y 2 , Y 3 , X 1 , X 2 , R 6 , and W, and C rings are as defined in any one of claims 1-19 and any one of item numbers 1-186 of U.S. Utility Patent Application No. 17 / 376,823, filed July 15, 2021, the entire contents of which are incorporated herein by reference.

[0303] In certain embodiments, the STING antagonist is a compound described in Table C1 of U.S. Utility Patent Application No. 17 / 376,823, filed July 15, 2021, each of which is incorporated by reference in its entirety into this specification.

[0304] In some embodiments, the STING antagonist is a compound of formula (XXI), or a pharma- ceutically acceptable salt or tautomer thereof: TIFF2024502755000024.tif26128 formula, Z, Y 1 , Y 2 , Y 3 , X 1 , X 2 , R 6 , B ring, L B , L A , a1, and the C ring may be as defined anywhere in U.S. Utility Application No. 17 / 376,829, filed July 15, 2021; and U.S. Provisional Application No. 63 / 052,052, filed July 15, 2020, each of which is incorporated by reference in its entirety.

[0305] In some of these embodiments, Z, Y 1 , Y 2 , Y 3 , X 1 , X 2 , R 6 , B ring, L B , L A, a1, and the C ring are each as defined in any one of claims 1 to 17 and any one of item numbers 1 to 181 of U.S. Utility Patent Application No. 17 / 376,829, filed July 15, 2021, the entire contents of which are incorporated herein by reference.

[0306] In certain embodiments, the STING antagonist is a compound described in Table C1 of U.S. Utility Patent Application No. 17 / 376,829, filed July 15, 2021, each of which is incorporated by reference in its entirety into this specification.

[0307] In some embodiments, the STING antagonist is a compound of formula (XXII), or a pharma- ceutically acceptable salt or tautomer thereof: TIFF2024502755000025.tif26128 formula, Z, Y 1 , Y 2 , Y 3 , X 1 , X 2 , R 6 and B ring may be as defined anywhere in PCT / US2021 / 041758, filed July 15, 2021; and U.S. Provisional Application No. 63 / 052,083, filed July 15, 2020, each of which is incorporated by reference in its entirety.

[0308] In some of these embodiments, Z, Y 1 , Y 2 , Y 3 , X 1 , X 2 , R 6 and ring B are as defined in any one of claims 1-18 and item numbers 1-157 of PCT / US2021 / 041758, filed July 15, 2021, each of which is incorporated by reference in its entirety.

[0309] In certain embodiments, the STING antagonist is a compound described in Table C1 of PCT / US2021 / 041758, filed July 15, 2021, each of which is incorporated by reference in its entirety into this specification.

[0310] In some embodiments, the STING antagonist is a compound of formula (XXIII), or a pharma- ceutically acceptable salt or tautomer thereof: TIFF2024502755000026.tif27128 formula, X 1 , X 2 , X 3 , Y 1 , Y 2 , Y 3 , R 3 , R 4 , R 5 , R 6 , and m may each be as defined anywhere in U.S. Provisional Application No. 63 / 126,332, filed December 16, 2020, which is incorporated by reference in its entirety.

[0311] In some of these embodiments, X 1 , X 2 , X 3 , Y 1 , Y 2 , Y 3 , R 3 , R 4 , R 5 , R 6 , and m are as defined in any one of claims 1-20 and any one of item numbers 1-174 of U.S. Provisional Application No. 63 / 126,332, filed December 16, 2020, the entire contents of which are incorporated herein by reference.

[0312] In certain embodiments, the STING antagonist is a compound described in Table C1 of U.S. Provisional Application No. 63 / 126,332, filed December 16, 2020, each of which is incorporated by reference in its entirety into this specification.

[0313] In some embodiments, the STING antagonist is a compound of formula (XXIV), or a pharma- ceutically acceptable salt or tautomer thereof: TIFF2024502755000027.tif27128 formula, X 1 , X 2 , X 3 , Y 1 , Y 2 , Y 3 , R 3 , and the A ring may each be as defined anywhere in U.S. Provisional Application No. 63 / 126,286, filed December 16, 2020, which is incorporated by reference in its entirety.

[0314] In some of these embodiments, X 1 , X 2 , X 3 , Y 1 , Y 2 , Y 3 , R 3 and ring A are as defined in any one of claims 1-23 and any one of item numbers 1-183 of U.S. Provisional Application No. 63 / 126,286, filed December 16, 2020, the entireties of which are incorporated herein by reference.

[0315] In certain embodiments, the STING antagonist is a compound described in Table C1 of U.S. Provisional Application No. 63 / 126,286, filed December 16, 2020, each of which is incorporated by reference in its entirety into this specification.

[0316] In some embodiments, the STING antagonist is a compound of formula (M1) or a pharma- ceutically acceptable salt thereof: TIFF2024502755000028.tif26128 formula, The B ring is selected from the group consisting of (B-1), (B-2), and (B-3): TIFF2024502755000029.tif33170X 1 O, S, N, NR 2 , and C.R. 5selected from the group consisting of; X 2 O, S, N, NR 4 , and C.R. 5 selected from the group consisting of; Z, Y 1 , Y 2 , and Y 3 are each independently CR 1 , N, and N 2 selected from the group consisting of; Y 4 is C or N; each TIFF2024502755000030.tif2128 is independently a single or double bond, However, in (B-1), (B-2), and (B-3), X 1 and X 2 is a heteroaryl; ·(B-1) Medium, 6-membered ring TIFF2024502755000031.tif24128 is an aromatic ring; ·(B-2) Medium, 6-membered ring TIFF2024502755000032.tif20128 is an aromatic ring, and Z and Y in (B-2) 1 , Y 2 , Y 3 , and Y 4 one or more of are independently selected heteroatoms; ·(B-3) Medium, 6-membered ring TIFF2024502755000033.tif19128 is an aromatic ring; W is selected from the group consisting of: ·*C(=O)NR N , *C(=S)NR N , *C(=NR N )NR N , *C(=NCN)NR N , *C(=CNO2)NR N , *S(O) 1~2 NR N ; TIFF2024502755000034.tif21128; ·*C(=O), *S(O)2; TIFF2024502755000035.tif18128; and · TIFF2024502755000036.tif19128, where Q 2 is a bond, NR N -O-, -S-, and -O-; Each R N are independently H and R d and an asterisk denotes NR 6 represents the attachment point to; A is: (i) -(Y A1 ) n -Y A2 , where n is 0 or 1; Y A1 is 1 to 6 R a C which may be substituted with 1~6 is alkylene; Y A2 is: (a) 1 to 4 R b C, each of which may be substituted with 3~20 Cycloalkyl or C 3~20 Cycloalkenyl; (b) 1 to 4 R c C which may be substituted with 6~20 Aryl; (c) Heteroaryl of 5 to 20 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is 1 to 4 independently selected R c heteroaryl, optionally substituted with (d) Heterocyclyl or heterocycloalkenyl of 3 to 16 ring atoms, in which 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2and each of the heterocyclyl or heterocycloalkenyl rings is independently selected from the group consisting of 1 to 4 R b heterocyclyl or heterocycloalkenyl, optionally substituted with or, (ii) 1 to 6 independently selected R a C which may be substituted with 1~20 Alkyl; R 1 , R 1a , R 1b , R 1c , and R 1d are each independently H; halo; cyano; 1-2 R a C which may be substituted with 1~6 Alkyl; C 2~6 Alkenyl; C 2~6 Alkynyl; C 1~4 Haloalkyl; C 1~4 Alkoxy; C 1~4 Haloalkoxy; -L 3 -L 4 -R i ;-S(O) 1~2 (C 1~4 alkyl); -S(O)(=NH)(C 1~4 alkyl); SF5; -NR e R f ; -OH; oxo; -S(O) 1~2 (NR'R''); -C 1~4 Thioalkoxy; -NO2; -C(=O)(C 1~4 alkyl); -C(=O)O(C 1~4 alkyl); -C(=O)OH; and -C(=O)N(R')(R''); Each R 2 is independently selected from the group consisting of: (i) 1 to 2 independently selected R a C which may be substituted with 1~6 Alkyl; (ii) C 3~6 Cycloalkyl, C 3~6 Cycloalkenyl, or C6~10 Aryl; (iii) heterocyclyl or heterocycloalkenyl of 3 to 10 ring atoms, in which 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 heterocyclyl or heterocycloalkenyl, each heteroatom independently selected from the group consisting of: (iv) Heteroaryl of 5 to 10 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 heteroaryl, each heteroatom independently selected from the group consisting of: (v) -C(O)(C 1~4 alkyl); -C(O)O(C 1~4 alkyl); -CON(R')(R''); -S(O) 1~2 (NR'R''); -S(O) 1~2 (C 1~4 alkyl); -OH; C 1~4 Alkoxy; and (vi) H; R 4 is H, and 1 to 3 independently selected R a C which may be substituted with 1~6 selected from the group consisting of alkyl; R 5 H; halo; -OH; -C 1~4 Alkyl; -C 1~4 Haloalkyl; C 1~4 Alkoxy; C 1~4 Haloalkoxy; -C(=O)O(C 1~4 alkyl); -C(=O)(C 1~4 alkyl); -C(=O)OH; -CON(R')(R''); -S(O) 1~2 (NR'R''); -S(O) 1~2 (C 1~4 alkyl; cyano; and 1 to 4 independently selected C 1~4 C, each of which may be substituted with alkyl 3~6 Cycloalkyl or C 3~6cycloalkenyl; R 6 is H; 1 to 3 independently selected R a C which may be substituted with 1~6 Alkyl; -OH; C 1~4 Alkoxy; C(=O)H; C(=O)(C 1~4 alkyl); 1 to 4 independently selected C 1~4 C optionally substituted with alkyl 6~10 Aryl; and heteroaryl of 5 to 10 ring atoms, 1 to 4 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is 1 to 4 independently selected C 1~4 heteroaryl optionally substituted with alkyl; Each R a are independently -OH; -F; -Cl; -Br; -NR e R f ; C 1~4 Alkoxy; C 1~4 Haloalkoxy; -C(=O)O(C 1~4 alkyl); -C(=O)(C 1~4 alkyl); -C(=O)OH; -CON(R')(R''); -S(O) 1~2 (NR'R''); -S(O) 1~2 (C 1~4 alkyl; cyano; and 1 to 4 independently selected C 1~4 C, each of which may be substituted with alkyl 3~6 Cycloalkyl or C 3~6 cycloalkenyl; Each R b independently represents 1 to 6 independently selected R a C which may be substituted with 1~10 Alkyl; C 1~4 Haloalkyl; -OH; oxo; -F; -Cl; -Br; -NR e R f ; C 1~4 Alkoxy; C1~4 Haloalkoxy; -C(=O)(C 1~10 alkyl); -C(=O)O(C 1~4 alkyl); -C(=O)OH; -C(=O)N(R')(R''); -S(O) 1~2 (NR'R''); -S(O) 1~2 (C 1~4 alkyl); and cyano; Each R c are independently halo; cyano; 1 to 6 independently selected R a C which may be substituted with 1~10 Alkyl; C 2~6 Alkenyl; C 2~6 Alkynyl; oxo; 1 to 2 independently selected R a C which may be substituted with 1~4 Alkoxy; C 1~4 Haloalkoxy; -S(O) 1~2 (C 1~4 Alkyl) or -S(O) 1~2 (C 1~4 haloalkyl); -NR e R f -OH; -S(O) 1~2 (NR'R''); -C 1~4 Thioalkoxy or -C 1~4 Thiohaloalkoxy; -NO2; -SF5; -C(=O)(C 1~10 alkyl); -C(=O)O(C 1~4 alkyl); -C(=O)OH; -C(=O)N(R')(R''); and -L 1 -L 2 -R h selected from the group consisting of; R d C may be substituted with 1 to 3 substituents each independently selected from the group consisting of halo and OH. 1~6 C, each of which may be substituted with 1 to 3 substituents independently selected from the group consisting of alkyl, halo, and OH; 3~6 Cycloalkyl or C 3~6 Cycloalkenyl; -C(O)(C 1~4alkyl); -C(O)O(C 1~4 alkyl); -CON(R')(R''); -S(O) 1~2 (NR'R''); -S(O) 1~2 (C 1~4 alkyl); -OH; and C 1~4 alkoxy; R e and R f are each independently H; C 1~6 Alkyl; C 1~6 Haloalkyl; C 3~6 Cycloalkyl or C 3~6 Cycloalkenyl; -C(O)(C 1~4 alkyl); -C(O)O(C 1~4 alkyl); -CON(R')(R''); -S(O) 1~2 (NR'R''); -S(O) 1~2 (C 1~4 alkyl); -OH; and C 1~4 alkoxy; or R e and R f are, together with the nitrogen atom to which they are attached, a ring of 3 to 8 ring atoms, (a) H and C 1~3 (b) N(R d ), 0 to 3 ring heteroatoms (R e and R f (other than the nitrogen atom bonded to) forms a ring; -L 1 is a bond or C 1~3 is alkylene; -L 2 -O-, -N(H)-, -N(C 1~3 Alkyl)-, -S(O) 0~2 - or in combination; -L 3 is a bond or C 1~3 is alkylene; -L 4-O-, -N(H)-, -N(C 1~3 Alkyl)-, -S(O) 0~2 - or in combination; R h and R i are each independently selected from the group consisting of: C 3~8 Cycloalkyl or C 3~8 cycloalkenyl, halo; 1 to 2 independently selected R a C which may be substituted with 1~4 Alkyl; C 1~4 Haloalkyl; Cyano; C 1~4 Alkoxy; and C 1~4 haloalkoxy, each of which is optionally substituted with 1 to 4 substituents independently selected from the group consisting of C 3~8 Cycloalkyl or C 3~8 Cycloalkenyl; Heterocyclyl or heterocycloalkenyl having 3 to 16 ring atoms, where 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and heterocyclyl or heterocycloalkenyl is halo; 1 to 2 independently selected R a C which may be substituted with 1~4 Alkyl; C 1~4 Haloalkyl; Cyano; C 1~4 Alkoxy; and C 1~4 heterocyclyl or heterocycloalkenyl, optionally substituted by 1 to 4 substituents independently selected from the group consisting of haloalkoxy; Heteroaryl with 5 to 10 ring atoms, 1 to 4 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is halo; 1 to 2 independently selected R a C which may be substituted with 1~4 Alkyl; C 1~4 Haloalkyl; Cyano; C1~4 Alkoxy; and C 1~4 heteroaryl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy; and C 6~10 aryl, halo; 1 to 2 independently selected R a C which may be substituted with 1~4 Alkyl; C 1~4 Haloalkyl; Cyano; C 1~4 Alkoxy; and C 1~4 haloalkoxy, C 6~10 Aryl; R' and R'' are each independently H, C 1~4 Alkyl, C 6~10 Aryl, halo, C 1~4 Alkyl, and C 1~4 haloalkyl, C 6~10 Aryl and heteroaryl of 5-10 ring atoms, where 1-4 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is selected from the group consisting of halo, -OH, NH, NH(C 1~4 alkyl), N(C 1~4 Alkyl)2, C 1~4 Alkyl, and C 1~4 haloalkyl; or R′ and R″, taken together with the nitrogen atom to which they are each attached, are a ring of 3 to 8 ring atoms, including (a) H and C 1~3 (b) 1 to 7 ring carbon atoms, each substituted with 1 to 2 substituents independently selected from the group consisting of alkyl, N(H), N(C 1~6 R′ and R″ are each independently selected from the group consisting of alkyl, O, and S.

[0317] In certain embodiments of formula (M1), the B ring is (B-2) (e.g. TIFF2024502755000037.tif24128, for example TIFF2024502755000038.tif21128); W is *C(=O)NR N , *C(=S)NR N , *C(=NR N )NR N , *C(=NCN)NR N , *C(=CNO2)NR N , *S(O) 1~2 NR N ; TIFF2024502755000039.tif21128 (e.g. C(=O)NR N , for example, C(=O)NH).

[0318] In certain embodiments of formula (M1), the B ring is (B-1) (e.g. TIFF2024502755000040.tif27128, for example TIFF2024502755000041.tif23128); or (B-2) (e.g. TIFF2024502755000042.tif24128, for example TIFF2024502755000043.tif21128); W is *C(=O).

[0319] In certain embodiments of formula (M1), the B ring is (B-1) (e.g. TIFF2024502755000044.tif27128, for example TIFF2024502755000045.tif26128); or (B-2) (e.g. TIFF2024502755000046.tif27128, for example TIFF2024502755000047.tif23128); W is *S(O)2 or The file is TIFF2024502755000048.tif17128.

[0320] In certain embodiments of formula (M1), the B ring is (B-1) (e.g. TIFF2024502755000049.tif27128, for example TIFF2024502755000050.tif26128); or (B-2) (e.g. TIFF2024502755000051.tif27128, for example TIFF2024502755000052.tif23128); W is TIFF2024502755000053.tif17128 (for example TIFF2024502755000054.tif18128).

[0321] In certain embodiments of formula (M1), the B ring is (B-3) (e.g. TIFF2024502755000055.tif23128, for example TIFF2024502755000056.tif23128); W is C(=O)NR N (e.g., C(=O)NH).

[0322] In certain embodiments of formula (M1), the B ring is (B-1) (e.g. TIFF2024502755000057.tif27128, for example TIFF2024502755000058.tif26128); W is C(=O)NR N (e.g., C(=O)NH); R 1a , R 1b , R 1c , and R 1d One of the following (e.g. R 1b ) is -L 3 -L 4 -R i (For example, -R i ).

[0323] In some embodiments, the STING antagonist is a compound of formula (M2) or a pharma- ceutically acceptable salt thereof: TIFF2024502755000059.tif26128 formula, W is defined according to (AA) or (BB) below: (AA) W is Q 1 -Q 2 -A, where Q 1 is selected from the group consisting of: (a) 1 to 2 independently selected R q1 phenyl optionally substituted with; (b) Heteroaryl containing 5-6 ring atoms, 1-4 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is 1 to 4 independently selected R q1 heteroaryl, optionally substituted with Q 2 is a bond, -NH-, -N(C 1~3 Alkyl)-, -O-, -C(=O), and -S(O) 0~2 - selected from the group consisting of; A is as defined herein for formula (M1); or (BB) W is selected from the group consisting of: (a) 1 to 4 R c C which may be substituted with 7~20 bicyclic or polycyclic aryl; and (b) Bicyclic or polycyclic heteroaryl containing 7 to 20 ring atoms, 1 to 4 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is 1 to 4 independently selected R c heteroaryl, optionally substituted with Each Rq1 (a) halo; (b) cyano; (c) 1 to 6 independently selected R a C which may be substituted with 1~10 Alkyl; (d) C 2~6 alkenyl; (e) C 2~6 Alkynyl; (f) C 3~6 Cycloalkyl; (g) C 1~4 Alkoxy; (h) C 1~4 Haloalkoxy; (i) -S(O) 1~2 (C 1~4 (j) -NR e R f (k) -OH; (l) -S(O) 1~2 (NR'R''); (m) -C 1~4 Thioalkoxy; (n) -NO2; (o) -C(=O)(C 1~4 (p) -C(=O)O(C 1~4 alkyl; (q) -C(=O)OH; (r) -C(=O)N(R')(R''); and (s) oxo; B ring, R 6 , R a , R c , R d , R e , R f , R′, and R″ are each as defined herein for formula (M1).

[0324] In certain embodiments of formula (M2), the B ring is (B-3) (e.g. TIFF2024502755000060.tif23128, for example TIFF2024502755000061.tif23128).

[0325] In certain embodiments of formula (M2), the B ring is (B-1) (e.g. TIFF2024502755000062.tif27128, for example TIFF2024502755000063.tif26128); or (B-2) (e.g. TIFF2024502755000064.tif27128, for example TIFF2024502755000065.tif23128).

[0326] In some embodiments, the STING antagonist is a compound of formula (M3), or a pharma- ceutically acceptable salt or tautomer thereof: TIFF2024502755000066.tif44128 formula, X 1 O, S, N, NR 2 , and C.R. 5 selected from the group consisting of; X 2 O, S, N, NR 4 , and C.R. 5 selected from the group consisting of; each TIFF2024502755000067.tif2128 is independently a single bond or a double bond, except that X 1 and X 2 is a heteroaryl; 6-membered ring TIFF2024502755000068.tif24128 is an aromatic ring; QA is defined according to either (A) or (B) below: (A) Q is NH, and C 1~6 R is 1 to 2 independently selected alkyl groups. a N(C 1~6 alkyl); A is: (i) -(Y A1 ) n -Y A2 , where n is 0 or 1; Y A1 is C 1~6 alkylene, optionally substituted with 1 to 6 substituents each independently selected from the group consisting of: ○Oxo; ○Ra ; ○1 to 4 independently selected C 1~4 C optionally substituted with alkyl 6~10 Aryl; and Heteroaryl with 5 to 10 ring atoms, 1 to 4 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is 1 to 4 independently selected C 1~4 heteroaryl, optionally substituted with alkyl; or Y A1 -Y A3 -Y A4 -Y A5 and Y A3 is connected to Q by ○Y A3 is oxo and R a C which may be substituted with 1 to 2 substituents each independently selected from the group consisting of 1~3 is alkylene; ○Y A4 -O-, -NH-, -N(C 1~6 alkyl)-, or -S-; ○Y A5 is a bond or 1 to 2 independently selected R a C which may be substituted with 1~3 is alkylene; Y A2 is: (a) 1 to 4 R b C, each of which may be substituted with 3~20 Cycloalkyl or C 3~20 Cycloalkenyl; (b) 1 to 4 R c C which may be substituted with 6~20 Aryl; (c) Heteroaryl of 5 to 20 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2and the heteroaryl ring is 1 to 4 independently selected R c heteroaryl, optionally substituted with (d) Heterocyclyl or heterocycloalkenyl of 3 to 16 ring atoms, in which 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and each of the heterocyclyl or heterocycloalkenyl rings is independently selected from the group consisting of 1 to 4 R b heterocyclyl or heterocycloalkenyl, optionally substituted with or, (ii) -Z 1 -Z 2 -Z 3 , where Z 1 is 1 to 4 R a C which may be substituted with 1~3 is alkylene; Z 2 -N(H)-, -N(R d )-, -O-, or -S-; Z 3 is 1 to 4 R a C which may be substituted with 2~7 is alkyl; or, (iii) 1 to 6 independently selected R a C which may be substituted with 1~20 Alkyl, or, (B) Q and A together Form TIFF2024502755000069.tif14128; E is a ring of 3-16 ring atoms, 0-3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and each independently selected heteroatom (other than the nitrogen atom already present) is a ring having 1 to 4 independently selected Rb is a ring, optionally substituted with R 1a , R 1b , R 1c , and R 1d are each independently H; halo; cyano; 1-2 R a C which may be substituted with 1~6 Alkyl; C 2~6 Alkenyl; C 2~6 Alkynyl; C 1~4 Haloalkyl; C 1~4 Alkoxy; C 1~4 Haloalkoxy; -L 3 -L 4 -R i ;-S(O) 1~2 (C 1~4 alkyl); -S(O)(=NH)(C 1~4 alkyl); SF5; -NR e R f ; -OH; oxo; -S(O) 1~2 (NR'R''); -C 1~4 Thioalkoxy; -NO2; -C(=O)(C 1~4 alkyl); -C(=O)O(C 1~4 alkyl); -C(=O)OH; and -C(=O)N(R')(R''); or R 1a and R 1b , R 1b and R 1c , or R 1c and R 1d are, together with the atoms connecting them, a ring of 3-10 ring atoms, with 0-2 ring atoms being N, N(H), N(R d ), O, and S(O) 0~2 and the ring is C 1~6 Alkyl, halo, C 1~6 Haloalkyl, -OH, NR e R f , C 1~6 Alkoxy, and C 1~6forming a ring which may be substituted by 1 to 4 substituents each independently selected from the group consisting of haloalkoxy; Each R 2 is independently selected from the group consisting of: (i) 1 to 2 independently selected R a C which may be substituted with 1~6 Alkyl; (ii) C 3~6 Cycloalkyl, C 3~6 Cycloalkenyl, or C 6~10 Aryl; (iii) heterocyclyl or heterocycloalkenyl of 3 to 10 ring atoms, in which 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 heterocyclyl or heterocycloalkenyl, each heteroatom independently selected from the group consisting of: (iv) Heteroaryl of 5 to 10 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 heteroaryl, each heteroatom independently selected from the group consisting of: (v) -C(O)(C 1~4 alkyl); -C(O)O(C 1~4 alkyl); -CON(R')(R''); -S(O) 1~2 (NR'R''); -S(O) 1~2 (C 1~4 alkyl); -OH; C 1~4 Alkoxy; and (vi) H; R 4 is H, and 1 to 3 independently selected R a C which may be substituted with 1~6 selected from the group consisting of alkyl; R 5 H; halo; -OH; -C 1~4 Alkyl; -C 1~4 Haloalkyl; C 1~4 Alkoxy; C 1~4 Haloalkoxy; -C(=O)O(C1~4 alkyl); -C(=O)(C 1~4 alkyl); -C(=O)OH; -CON(R')(R''); -S(O) 1~2 (NR'R''); -S(O) 1~2 (C 1~4 alkyl; cyano; and 1 to 4 independently selected C 1~4 C, each of which may be substituted with alkyl 3~6 Cycloalkyl or C 3~6 cycloalkenyl; R 6 is H; 1 to 3 independently selected R a C which may be substituted with 1~6 Alkyl; -OH; C 1~4 Alkoxy; C(=O)H; C(=O)(C 1~4 alkyl); 1 to 4 independently selected C 1~4 C optionally substituted with alkyl 6~10 Aryl; and heteroaryl of 5 to 10 ring atoms, 1 to 4 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is 1 to 4 independently selected C 1~4 heteroaryl optionally substituted with alkyl; Each R a are independently -OH; -F; -Cl; -Br; -NR e R f ; C 1~4 Alkoxy; C 1~4 Haloalkoxy; -C(=O)O(C 1~4 alkyl); -C(=O)(C 1~4 alkyl); -C(=O)OH; -CON(R')(R''); -S(O) 1~2 (NR'R''); -S(O) 1~2 (C 1~4 alkyl; cyano; and 1 to 4 independently selected C 1~4 C, each of which may be substituted with alkyl 3~6Cycloalkyl or C 3~6 cycloalkenyl; Each R b independently represents 1 to 6 independently selected R a C which may be substituted with 1~10 Alkyl; C 1~4 Haloalkyl; -OH; oxo; -F; -Cl; -Br; -NR e R f ; C 1~4 Alkoxy; C 1~4 Haloalkoxy; -C(=O)(C 1~10 alkyl); -C(=O)O(C 1~4 alkyl); -C(=O)OH; -C(=O)N(R')(R''); -S(O) 1~2 (NR'R''); -S(O) 1~2 (C 1~4 alkyl; cyano; and -L 1 -L 2 -R h selected from the group consisting of; Each R c are independently halo; cyano; 1 to 6 independently selected R a C which may be substituted with 1~10 Alkyl; C 2~6 Alkenyl; C 2~6 Alkynyl; oxo; 1 to 2 independently selected R a C which may be substituted with 1~4 Alkoxy; C 1~4 Haloalkoxy; -S(O) 1~2 (C 1~4 Alkyl) or -S(O) 1~2 (C 1~4 haloalkyl); -NR e R f -OH; -S(O) 1~2 (NR'R''); -C 1~4 Thioalkoxy or -C 1~4 Thiohaloalkoxy; -NO2; -SF5; -C(=O)(C 1~10 alkyl); -C(=O)O(C 1~4alkyl); -C(=O)OH; -C(=O)N(R')(R''); and -L 1 -L 2 -R h selected from the group consisting of; R d C may be substituted with 1 to 3 substituents each independently selected from the group consisting of halo and OH. 1~6 C, each of which may be substituted with 1 to 3 substituents independently selected from the group consisting of alkyl, halo, and OH; 3~6 Cycloalkyl or C 3~6 Cycloalkenyl; -C(O)(C 1~4 alkyl); -C(O)O(C 1~4 alkyl); -CON(R')(R''); -S(O) 1~2 (NR'R''); -S(O) 1~2 (C 1~4 alkyl); -OH; and C 1~4 alkoxy; R e and R f are each independently H; C 1~6 Alkyl; C 1~6 Haloalkyl; C 3~6 Cycloalkyl or C 3~6 Cycloalkenyl; -C(O)(C 1~4 alkyl); -C(O)O(C 1~4 alkyl); -CON(R')(R''); -S(O) 1~2 (NR'R''); -S(O) 1~2 (C 1~4 alkyl); -OH; and C 1~4 alkoxy; or R e and R f are, together with the nitrogen atom to which they are attached, a ring of 3 to 8 ring atoms, (a) H and C 1~3 (b) N(R d), 0 to 3 ring heteroatoms (R e and R f (other than the nitrogen atom bonded to) forms a ring; -L 1 is a bond or C 1~3 is alkylene; -L 2 -O-, -N(H)-, -N(C 1~3 Alkyl)-, -S(O) 0~2 - or in combination; R h is selected from the group consisting of: C 3~8 Cycloalkyl or C 3~8 cycloalkenyl, halo; 1 to 2 independently selected R a C which may be substituted with 1~4 Alkyl; C 1~4 Haloalkyl; Cyano; C 1~4 Alkoxy; and C 1~4 haloalkoxy, each of which is optionally substituted with 1 to 4 substituents independently selected from the group consisting of C 3~8 Cycloalkyl or C 3~8 Cycloalkenyl; Heterocyclyl or heterocycloalkenyl having 3 to 16 ring atoms, where 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and heterocyclyl or heterocycloalkenyl is halo; 1 to 2 independently selected R a C which may be substituted with 1~4 Alkyl; C 1~4 Haloalkyl; Cyano; C 1~4 Alkoxy; and C 1~4 heterocyclyl or heterocycloalkenyl, optionally substituted by 1 to 4 substituents independently selected from the group consisting of haloalkoxy; Heteroaryl with 5 to 10 ring atoms, 1 to 4 of which are N, N(H), N(R d), O, and S(O) 0~2 and the heteroaryl ring is halo; 1 to 2 independently selected R a C which may be substituted with 1~4 Alkyl; C 1~4 Haloalkyl; Cyano; C 1~4 Alkoxy; and C 1~4 heteroaryl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy; and C 6~10 aryl, halo; 1 to 2 independently selected R a C which may be substituted with 1~4 Alkyl; C 1~4 Haloalkyl; Cyano; C 1~4 Alkoxy; and C 1~4 haloalkoxy, C 6~10 Aryl; -L 3 is a bond or C 1~3 is alkylene; -L 4 -O-, -N(H)-, -N(C 1~3 Alkyl)-, -S(O) 0~2 - or in combination; R i is selected from the group consisting of: C 3~8 Cycloalkyl or C 3~8 cycloalkenyl, halo; 1 to 2 independently selected R a C which may be substituted with 1~4 Alkyl; C 1~4 Haloalkyl; Cyano; C 1~4 Alkoxy; and C 1~4 haloalkoxy, each of which is optionally substituted with 1 to 4 substituents independently selected from the group consisting of C 3~8 Cycloalkyl or C 3~8 Cycloalkenyl; Heterocyclyl or heterocycloalkenyl having 3 to 16 ring atoms, where 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and heterocyclyl or heterocycloalkenyl is halo; 1 to 2 independently selected R a C which may be substituted with 1~4 Alkyl; C 1~4 Haloalkyl; Cyano; C 1~4 Alkoxy; and C 1~4 heterocyclyl or heterocycloalkenyl, optionally substituted by 1 to 4 substituents independently selected from the group consisting of haloalkoxy; Heteroaryl with 5 to 10 ring atoms, 1 to 4 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is halo; 1 to 2 independently selected R a C which may be substituted with 1~4 Alkyl; C 1~4 Haloalkyl; Cyano; C 1~4 Alkoxy; and C 1~4 heteroaryl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy; and C 6~10 aryl, halo; 1 to 2 independently selected R a C which may be substituted with 1~4 Alkyl; C 1~4 Haloalkyl; Cyano; C 1~4 Alkoxy; and C 1~4 haloalkoxy, C 6~10 Aryl; R' and R'' are each independently H, C 1~4 Alkyl, C 6~10 Aryl, halo, C 1~4 Alkyl, and C 1~4haloalkyl, C 6~10 Aryl and heteroaryl of 5-10 ring atoms, where 1-4 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is selected from the group consisting of halo, -OH, NH, NH(C 1~4 alkyl), N(C 1~4 Alkyl)2, C 1~4 Alkyl, and C 1~4 haloalkyl; or R′ and R″, taken together with the nitrogen atom to which they are each attached, are a ring of 3 to 8 ring atoms, including (a) H and C 1~3 (b) 1 to 7 ring carbon atoms, each substituted with 1 to 2 substituents independently selected from the group consisting of alkyl, N(H), N(C 1~6 R′ and R″ are each independently selected from the group consisting of alkyl, O, and S.

[0327] In certain embodiments of formula (M3), the compound is of formula (M3A) or a pharma- ceutically acceptable salt thereof: TIFF2024502755000070.tif70128 formula, m1 and m2 are independently 0, 1, or 2; Q 5 is N or CH; L 5 is a bond, CH2, -O-, -N(H)-, or -N(C 1~3 alkyl), except that Q 5 If N, then L 5 is a bond or CH2; T 1 , T 2 , T 3 , and T 4 are each independently N, CH, or CR tHowever, T 1 ~T 4 of which 1 to 4, e.g., 2, 3, or 4, are CH; R t and R s are each independently halo; 1 to 2 independently selected R a C which may be substituted with 1~4 Alkyl; C 1~4 Haloalkyl; Cyano; C 1~4 Alkoxy; and C 1~4 haloalkoxy; Optionally, R 2 is H and R 5 is H; Optionally, R 1b is halo, e.g., -F or -Cl; R 1c is H or halo, e.g., -H or -F; R 1a and R 1d is H.

[0328] In some embodiments, the STING antagonist is a compound of formula (M4), or a pharma- ceutically acceptable salt or tautomer thereof: TIFF2024502755000071.tif42128 formula, Z is CR 1 , N, and N 2 selected from the group consisting of; Y 1 , Y 2 , and Y 3 are each independently CR 1 , N, and N 2 selected from the group consisting of; Y 4 is C or N, except for Z, Y 1 , Y 2 , Y 3 , and Y 4 one or more of are independently selected heteroatoms; X 1 O, S, N, NR 2 , and C.R. 1 selected from the group consisting of; X 2 O, S, N, NR 4 , and C.R. 5 selected from the group consisting of; each TIFF2024502755000072.tif2128 is independently a single bond or a double bond, except that Y 4 , X 1 , and X 2 The five-membered ring containing Z, Y is heteroaryl. 1 , Y 2 , and Y 3 is a heteroaryl; Each R 1 are independently H; halo; cyano; 1-2 R a C which may be substituted with 1~6 Alkyl; C 2~6 Alkenyl; C 2~6 Alkynyl; C 1~4 Haloalkyl; C 1~4 Alkoxy; C 1~4 Haloalkoxy; -L 3 -L 4 -R i ;-S(O) 1~2 (C 1~4 alkyl); -S(O)(=NH)(C 1~4 alkyl); SF5; -NR e R f ; -OH; oxo; -S(O) 1~2 (NR'R''); -C 1~4 Thioalkoxy; -NO2; -C(=O)(C 1~4 alkyl); -C(=O)O(C 1~4 alkyl); -C(=O)OH; and -C(=O)N(R')(R''); R 2 , R 4 , R 5 , R 6 , Q, A, R a , R e , R f , L 3 , L 4 , R i, R', and R'' are each as defined herein for formula M3.

[0329] In some embodiments, the STING antagonist is a compound of formula (M5), or a pharma- ceutically acceptable salt or tautomer thereof: TIFF2024502755000073.tif44128 formula, X 1 O, S, N, NR 2 , and C.R. 1 selected from the group consisting of; X 2 O, S, N, NR 4 , and C.R. 5 selected from the group consisting of; each TIFF2024502755000074.tif2128 is independently a single bond or a double bond, provided that: X 1 and X 2 is a heteroaryl; 6-membered ring TIFF2024502755000075.tif30128 is an aromatic ring; P 1 , P 2 , P 3 , P 4 , and P 5 is an aromatic ring; P 1 , P 2 , P 3 , P 4 , and P 5 is defined according to (AA) or (BB): (AA) P 1 , P 2 , P 3 , P 4 , and P 5 are independently N, CH, or CR 7 , and C.R. c With the proviso that P 1 , P 2 , P 3 , P 4, and P 5 One or two of the CRs are selected independently. 7 or (BB) P 1 is not present, which results in a five-membered ring, P 2 , P 3 , P 4 , and P 5 are each independently O, S, N, NH, or NR d , N.R. 7 , C.H., C.R. 7 , and C.R. c With the proviso that P 2 , P 3 , P 4 , and P 5 Of these, 1 to 3 are O, S, N, NH, or NR. d , or N.R. 7 And;P 2 , P 3 , P 4 , and P 5 One or two of these are selected independently. 7 or CR 7 is; Each R 7 is independently -R 8 and -L 3 -R 9 selected from the group consisting of; R 8 and R 9 is independently selected from the group consisting of: (a) 1 to 4 independently selected R 7 ', each of which may be substituted with C 3~12 Cycloalkyl or C 3~12 Cycloalkenyl; (b) Heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, in which 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2and one or more ring carbon atoms of the heterocyclyl or heterocycloalkenyl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7 ', optionally substituted with heterocyclyl or heterocycloalkenyl; (c) Heteroaryl of 5 to 12 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heteroaryl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7 ', optionally substituted with heteroaryl; and (d) 1 to 4 independently selected R 7 ' may be substituted with C 6~10 Aryl; -L 3 -O-, -CH2-, -S-, -NH-, S(O) 1~2 , C(=O)NH, NHC(=O), C(=O)O, OC(=O), C(=O), NHS(O)2, and S(O)2NH; Each R 7 ' is independently halo; -CN; -NO2; -OH; 1 to 2 independently selected R a -C 1~4 Alkyl; -C 2~4 Alkenyl; -C 2~4 Alkynyl; -C 1~4 Haloalkyl; 1 to 2 independently selected R a -C 1~6 Alkoxy; -C 1~6 Haloalkoxy; S(O) 1~2 (C 1~4 alkyl); -NR'R''; oxo; -S(O) 1~2 (NR'R''); -C 1~4 Thioalkoxy; -C(=O)(C 1~4 alkyl); -C(=O)O(C 1~4alkyl); -C(=O)OH; and -C(=O)N(R')(R''); W is (i) C(=O); (ii) C(=S); (iii) S(O). 1~2 (iv) C(=NR d ) or C(=N-CN); (v) C(=NH); (vi) C(=C-NO2); (vii) S(=O)(=N(R d )); and (viii) S(=O)(=NH); Q is NH, N(C 1~6 alkyl), *-NH-(C 1~3 alkylene)-, and *-N(C 1~6 Alkyl)-(C 1~3 alkylene)-, where C 1~6 Alkyl is one to two independently selected R a where the asterisk represents the point of attachment to W; R 1a , R 1b , R 1c , and R 1d are each independently H; halo; cyano; 1-2 R a C which may be substituted with 1~6 Alkyl; C 2~6 Alkenyl; C 2~6 Alkynyl; C 1~4 Haloalkyl; C 1~4 Alkoxy; C 1~4 Haloalkoxy; -S(O) 1~2 (C 1~4 alkyl); -S(O)(=NH)(C 1~4 alkyl); SF5; -NR e R f -OH; -S(O) 1~2 (NR'R''); -C 1~4 Thioalkoxy; -NO2; -C(=O)(C 1~4 alkyl); -C(=O)O(C 1~4 alkyl); -C(=O)OH; and -C(=O)N(R')(R''); Each R 2is independently selected from the group consisting of: (i) H; (ii) 1 to 3 independently selected R a C which may be substituted with 1~6 Alkyl; (iii) 1 to 3 independently selected R a -C(O)(C 1~6 alkyl); (iv) 1 to 3 independently selected R a may be substituted with -C(O)O(C 1~4 alkyl); (v) -CON(R')(R''); (vi) -S(O) 1~2 (NR'R''); (vii) 1 to 3 independently selected R a -S(O) optionally substituted with 1~2 (C 1~4 alkyl); (viii) -OH; (ix) C 1~4 Alkoxy; and (x) -L 4 -L 5 -R i ; R 4 is H, and 1 to 3 independently selected R a C which may be substituted with 1~6 selected from the group consisting of alkyl; R 5 H; halo; -OH; -C 1~4 Alkyl; -C 1~4 Haloalkyl; C 1~4 Alkoxy; C 1~4 Haloalkoxy; -C(=O)O(C 1~4 alkyl); -C(=O)(C 1~4 alkyl); -C(=O)OH; -CON(R')(R''); -S(O) 1~2 (NR'R''); -S(O) 1~2 (C 1~4 alkyl; cyano; and 1 to 4 independently selected C 1~4C, each of which may be substituted with alkyl 3~6 Cycloalkyl or C 3~6 cycloalkenyl; R 6 is H; 1 to 3 independently selected R a C which may be substituted with 1~6 Alkyl; -OH; C 1~4 Alkoxy; C(=O)H; C(=O)(C 1~4 alkyl); 1 to 4 independently selected C 1~4 C optionally substituted with alkyl 6~10 Aryl; and heteroaryl of 5 to 10 ring atoms, 1 to 4 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is 1 to 4 independently selected C 1~4 heteroaryl optionally substituted with alkyl; Each R a are independently -OH; -F; -Cl; -Br; -NR e R f ; C 1~4 Alkoxy; C 1~4 Haloalkoxy; -C(=O)O(C 1~4 alkyl); -C(=O)(C 1~4 alkyl); -C(=O)OH; -CON(R')(R''); -S(O) 1~2 (NR'R''); -S(O) 1~2 (C 1~4 alkyl; cyano; and 1 to 4 independently selected C 1~4 C, each of which may be substituted with alkyl 3~6 Cycloalkyl or C 3~6 cycloalkenyl; Each R b independently represents 1 to 6 independently selected R a C which may be substituted with 1~10 Alkyl; C 1~4Haloalkyl; -OH; oxo; -F; -Cl; -Br; -NR e R f ; C 1~4 Alkoxy; C 1~4 Haloalkoxy; -C(=O)(C 1~10 alkyl); -C(=O)O(C 1~4 alkyl); -C(=O)OH; -C(=O)N(R')(R''); -S(O) 1~2 (NR'R''); -S(O) 1~2 (C 1~4 alkyl; cyano; and -L 1 -L 2 -R h selected from the group consisting of; Each R c are independently halo; cyano; 1 to 6 independently selected R a C which may be substituted with 1~10 Alkyl; C 2~6 Alkenyl; C 2~6 Alkynyl; C 1~4 Alkoxy; C 1~4 Haloalkoxy; -S(O) 1~2 (C 1~4 alkyl); -NR e R f -OH; -S(O) 1~2 (NR'R''); -C 1~4 Thioalkoxy; -NO2; -C(=O)(C 1~10 alkyl); -C(=O)O(C 1~4 alkyl); -C(=O)OH; -C(=O)N(R')(R''); and -L 1 -L 2 -R h selected from the group consisting of; R d Halo, C 1~3 Alkoxy, C 1~3 C which may be substituted by 1 to 3 substituents independently selected from the group consisting of haloalkoxy and OH; 1~6 C, each of which may be substituted with 1 to 3 substituents independently selected from the group consisting of alkyl, halo, and OH; 3~6Cycloalkyl or C 3~6 Cycloalkenyl; -C(O)(C 1~4 alkyl); -C(O)O(C 1~4 alkyl); -CON(R')(R''); -S(O) 1~2 (NR'R''); -S(O) 1~2 (C 1~4 alkyl); -OH; and C 1~4 alkoxy; R e and R f are each independently H; C 1~6 Alkyl; C 1~6 Haloalkyl; C 3~6 Cycloalkyl or C 3~6 Cycloalkenyl; -C(O)(C 1~4 alkyl); -C(O)O(C 1~4 alkyl); -CON(R')(R''); -S(O) 1~2 (NR'R''); -S(O) 1~2 (C 1~4 alkyl); -OH; and C 1~4 alkoxy; or R e and R f are, together with the nitrogen atom to which they are attached, a ring of 3 to 8 ring atoms, (a) H and C 1~3 (b) N(R d ), 0 to 3 ring heteroatoms (R e and R f (other than the nitrogen atom bonded to) forms a ring; -L 1 is a bond or C 1~3 -L is alkylene; 2 -O-, -N(H)-, -S(O) 0~2 - or in combination; R h is selected from the group consisting of: C 3~8Cycloalkyl or C 3~8 cycloalkenyl, halo; 1 to 2 independently selected R a C which may be substituted with 1~4 Alkyl; C 1~4 Haloalkyl; Cyano; C 1~4 Alkoxy; and C 1~4 haloalkoxy, each of which is optionally substituted with 1 to 4 substituents independently selected from the group consisting of C 3~8 Cycloalkyl or C 3~8 Cycloalkenyl; Heterocyclyl or heterocycloalkenyl having 3 to 16 ring atoms, where 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and heterocyclyl or heterocycloalkenyl is halo; 1 to 2 independently selected R a C which may be substituted with 1~4 Alkyl; C 1~4 Haloalkyl; Cyano; C 1~4 Alkoxy; and C 1~4 heterocyclyl or heterocycloalkenyl, optionally substituted by 1 to 4 substituents independently selected from the group consisting of haloalkoxy; Heteroaryl with 5 to 10 ring atoms, 1 to 4 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is halo; 1 to 2 independently selected R a C which may be substituted with 1~4 Alkyl; C 1~4 Haloalkyl; Cyano; C 1~4 Alkoxy; and C 1~4 heteroaryl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy; and C 6~10 aryl, halo; 1 to 2 independently selected R aC which may be substituted with 1~4 Alkyl; C 1~4 Haloalkyl; Cyano; C 1~4 Alkoxy; and C 1~4 haloalkoxy, C 6~10 Aryl; -L 4 - is a bond, -C(O)-, -C(O)O-, -C(O)NH-, C(O)NR d , S(O) 1~2 , S(O) 1~2 NH, and S(O) 1~2 NR d selected from the group consisting of; -L 5 - is a bond and C 1~4 alkylene; R i is selected from the group consisting of: C 3~8 Cycloalkyl or C 3~8 Cycloalkenyl, halo; OH; NR e R f ; 1 to 2 independently selected R a C which may be substituted with 1~4 Alkyl; C 1~4 Haloalkyl; Cyano; C 1~4 Alkoxy; and C 1~4 haloalkoxy, each of which is optionally substituted with 1 to 4 substituents independently selected from the group consisting of C 3~8 Cycloalkyl or C 3~8 Cycloalkenyl; Heterocyclyl or heterocycloalkenyl having 3 to 16 ring atoms, where 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and the heterocyclyl or heterocycloalkenyl is halo; OH; NR e R f ; 1 to 2 independently selected R a C which may be substituted with 1~4Alkyl; C 1~4 Haloalkyl; Cyano; C 1~4 Alkoxy; and C 1~4 heterocyclyl or heterocycloalkenyl, optionally substituted by 1 to 4 substituents independently selected from the group consisting of haloalkoxy; Heteroaryl with 5 to 10 ring atoms, 1 to 4 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is a heteroatom independently selected from the group consisting of halo; OH; NR e R f ; 1 to 2 independently selected R a C which may be substituted with 1~4 Alkyl; C 1~4 Haloalkyl; Cyano; C 1~4 Alkoxy; and C 1~4 heteroaryl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy; and C 6~10 Aryl, halo; OH; NR e R f ; 1 to 2 independently selected R a C which may be substituted with 1~4 Alkyl; C 1~4 Haloalkyl; Cyano; C 1~4 Alkoxy; and C 1~4 haloalkoxy, C 6~10 Aryl; R' and R'' are each independently H; -OH; C 1~4 Alkyl; C 6~10 Aryl, halo, C 1~4 Alkyl, and C 1~4 haloalkyl, C 6~10 Aryl; and heteroaryl of 5 to 10 ring atoms, 1 to 4 of which are N, N(H), N(R d ), O, and S(O)0~2 and the heteroaryl ring is selected from the group consisting of halo, -OH, NH, NH(C 1~4 alkyl), N(C 1~4 Alkyl)2, C 1~4 Alkyl, and C 1~4 haloalkyl; R' and R'', taken together with the nitrogen atom to which they are attached, form a ring of 3 to 8 ring atoms, (a) H and C 1~3 (b) 1 to 7 ring carbon atoms, each substituted with 1 to 2 substituents independently selected from the group consisting of alkyl, N(H), N(C 1~6 R′ and R″ are each independently selected from the group consisting of alkyl, O, and S.

[0330] In certain embodiments of formula (M5), the compound is of formula (M5-1a), (M5-2a), or (M5-3a), or a pharma- ceutically acceptable salt thereof: TIFF2024502755000076.tif63137In formula, R 1a , R 1b , R 1c , R 1d are each independently H; halo; cyano; 1-2 R a C which may be substituted with 1~6 Alkyl; C 1~4 Haloalkyl; C 1~4 Alkoxy; and C 1~4 haloalkoxy; n2 is 0, 1, or 2; Each R c When present, each independently represents halo, cyano, C 1~3 Alkyl, and C 1~3 alkoxy; R 8 is selected from the group consisting of: · TIFF2024502755000077.tif24128, where m1 and m2 are independently 0, 1, or 2, and T 1 is CH or N; and Spirocyclic heterocyclyl with 6 to 12 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heterocyclyl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7 Optionally substituted spirocyclic heterocyclyl.

[0331] In some embodiments, the STING antagonist is a compound of formula (M6), or a pharma- ceutically acceptable salt or tautomer thereof: TIFF2024502755000078.tif37128 formula, Z, Y 1 , Y 2 , and Y 3 are each independently CR 1 , N, and N 2 where Z, Y are each independently selected from the group consisting of 1 , Y 2 , and Y 3 One to three of these are independently selected N or NR 2 and; X 1 O, S, N, NR 2 , and C.R. 1 selected from the group consisting of; X 2 O, S, N, NR 4 , and C.R. 5 selected from the group consisting of; each TIFF2024502755000079.tif2128 is independently a single bond or a double bond, except that X 1 and X 2 The five-membered ring containing Z, Y is heteroaryl; 1 , Y 2 , and Y3 A six-membered ring containing is heteroaryl; 1 , P 2 , P 3 , P 4 , and P 5 is an aromatic ring; W is (i) C(=O); (ii) C(=S); (iii) S(O). 1~2 (iv) C(=NR d ) or C(=N-CN); (v) C(=NH); (vi) C(=C-NO2); (vii) S(=O)(=N(R d )); and (viii) S(=O)(=NH); Q is NH, N(C 1~6 alkyl), *-NH-(C 1~3 alkylene)-, and *-N(C 1~6 Alkyl)-(C 1~3 alkylene)-, where C 1~6 Alkyl is one to two independently selected R a where the asterisk represents the point of attachment to W; P 1 , P 2 , P 3 , P 4 , and P 5 is defined according to (AA) or (BB): (AA) P 1 , P 2 , P 3 , P 4 , and P 5 are independently N, CH, or CR 7 , and C.R. c With the proviso that P 1 , P 2 , P 3 , P 4 , and P 5 One or two of the CRs are selected independently. 7 or (BB) P 1 is not present, which results in a five-membered ring, P 2 , P 3 , P 4 , and P 5 are each independently O, S, N, NH, or NR d , N.R. 7 , C.H., C.R. 7 , and C.R. c is selected from the group consisting of; However, P 2 , P 3 , P 4 , and P 5 Of these, 1 to 3 are O, S, N, NH, or NR. d , or N.R. 7 and; P 2 , P 3 , P 4 , and P 5 One or two of these are selected independently. 7 or CR 7 is; Each R 7 is independently -R 8 and -L 3 -R 9 selected from the group consisting of; -R 8 is selected from the group consisting of: (a) 1 to 4 independently selected R 7 ' respectively replaced by C 3~12 Cycloalkyl or C 3~12 Cycloalkenyl; (b) Heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, in which 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heterocyclyl or heterocycloalkenyl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7 ', heterocyclyl or heterocycloalkenyl substituted with; (c) 1 to 4 independently selected C 1~4C3 cycloalkyl, C3 cycloalkenyl, C5 cycloalkyl, or C5 cycloalkenyl, each optionally substituted with alkyl; (d) 1 to 4 independently selected C 1~4 C, each of which may be substituted with alkyl 7~12 Cycloalkyl or C 7~12 Cycloalkenyl; (e) Heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, in which 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and wherein heterocyclyl is other than tetrahydropyranyl and one or more ring carbon atoms of the heterocyclyl ring or heterocycloalkenyl ring are each independently selected from the group consisting of 1 to 4 independently selected C 1~4 heterocyclyl or heterocycloalkenyl optionally substituted with alkyl; (f) Heteroaryl of 5 to 12 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heteroaryl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7 ', optionally substituted with heteroaryl; and (g) 1 to 4 independently selected R 7 ' may be substituted with C 6~10 Aryl; -L 3 -O-, -S-, -NH-, S(O) 1~2 , -CH2-, C(=O)NH, NHC(=O), C(=O)O, OC(=O), C(=O), NHS(O)2, and S(O)2NH; -R 9 is selected from the group consisting of: (a) 1 to 4 independently selected R 7 ', each of which may be substituted with C 3~12 Cycloalkyl or C 3~12Cycloalkenyl; (b) Heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, in which 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heterocyclyl or heterocycloalkenyl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7 ', optionally substituted with heterocyclyl or heterocycloalkenyl; (c) Heteroaryl of 5 to 12 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heteroaryl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7 ', optionally substituted with heteroaryl; and (d) 1 to 4 independently selected R 7 ' may be substituted with C 6~10 Aryl; Each R 7 ' is independently halo; -CN; -NO2; -OH; 1 to 2 independently selected R a -C 1~4 Alkyl; -C 2~4 Alkenyl; -C 2~4 Alkynyl; -C 1~4 Haloalkyl; 1 to 2 independently selected R a -C 1~6 Alkoxy; -C 1~6 Haloalkoxy; S(O) 1~2 (C 1~4 alkyl); -NR'R''; oxo; -S(O) 1~2 (NR'R''); -C 1~4 Thioalkoxy; -C(=O)(C 1~4 alkyl); -C(=O)O(C 1~4 alkyl; -C(=O)OH; and -C(=O)N(R')(R''); However, R 7 R 8 R 8 is cycloalkyl, cycloalkenyl, heterocyclyl, or heterocycloalkenyl, and 1 to 4 R 7 ' is substituted, R 8 is C 1~4 cannot be monosubstituted with alkyl, R 8 2 to 4 R 7 ', there is at least one R 7 ' is C 1~4 The substituent must be other than alkyl; Each R 1 are independently H; halo; cyano; 1-2 R a C which may be substituted with 1~6 Alkyl; C 2~6 Alkenyl; C 2~6 Alkynyl; C 1~4 Haloalkyl; C 1~4 Alkoxy; C 1~4 Haloalkoxy; -L 1 -L 2 -R h ;-S(O) 1~2 (C 1~4 alkyl); -S(O)(=NH)(C 1~4 alkyl); SF5; -NR e R f ; -OH; oxo; -S(O) 1~2 (NR'R''); -C 1~4 Thioalkoxy; -NO2; -C(=O)(C 1~4 alkyl); -C(=O)O(C 1~4 alkyl); -C(=O)OH; and -C(=O)N(R')(R''); Each R 2 is independently selected from the group consisting of: (i) H; (ii) 1 to 3 independently selected R a C which may be substituted with 1~6 Alkyl; (iii) 1 to 3 independently selected R a -C(O)(C 1~6 alkyl); (iv) 1 to 3 independently selected R a may be substituted with -C(O)O(C 1~4 alkyl); (v) -CON(R')(R''); (vi) -S(O) 1~2 (NR'R''); (vii) 1 to 3 independently selected R a -S(O) optionally substituted with 1~2 (C 1~4 alkyl); (viii) -OH; (ix) C 1~4 Alkoxy; and (x) -L 4 -L 5 -R i ; R 4 is H, and 1 to 3 independently selected R a C which may be substituted with 1~6 selected from the group consisting of alkyl; R 5 H; halo; -OH; -C 1~4 Alkyl; -C 1~4 Haloalkyl; C 1~4 Alkoxy; C 1~4 Haloalkoxy; -C(=O)O(C 1~4 alkyl); -C(=O)(C 1~4 alkyl); -C(=O)OH; -CON(R')(R''); -S(O) 1~2 (NR'R''); -S(O) 1~2 (C 1~4 alkyl; cyano; and 1 to 4 independently selected C 1~4 C, each of which may be substituted with alkyl 3~6 Cycloalkyl or C 3~6 cycloalkenyl; R 6 is H; 1 to 3 independently selected Ra C which may be substituted with 1~6 Alkyl; -OH; C 1~4 Alkoxy; C(=O)H; C(=O)(C 1~4 alkyl); 1 to 4 independently selected C 1~4 C optionally substituted with alkyl 6~10 Aryl; and heteroaryl of 5 to 10 ring atoms, 1 to 4 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is 1 to 4 independently selected C 1~4 heteroaryl optionally substituted with alkyl; R a , R b , R c , R d , R e , R f , -L 1 , -L 2 , R h , -L 4 , L 5 , -R i , R′, and R″ are each as defined in formula (M5) herein.

[0332] In certain embodiments of formula (M6), the compound is of formula (M6-3a) or (M6-3b), or a pharma- ceutically acceptable salt thereof: TIFF2024502755000080.tif30139In formula, R 1a , R 1b , and R 1c are each independently H; halo; cyano; 1-2 R a C which may be substituted with 1~6 Alkyl; C 1~4 Haloalkyl; C 1~4 Alkoxy; and C 1~4 haloalkoxy; Q 1 is N or CH; R 8teeth TIFF2024502755000081.tif33128; n2 is 0, 1, or 2; Each R c When present, each independently represents halo, cyano, C 1~3 Alkyl, and C 1~3 alkoxy; m1 and m2 are independently 0, 1, or 2; m3, m4, m5, and m6 are independently 0 or 1; T 1 is CH or N, Optionally, R 2 is H; Optionally, n2 is 1 and R c is R 8 is ortho to; Optionally, each R 7 ' is independently halo, e.g., -F.

[0333] In some embodiments, the STING antagonist is selected from the group consisting of the compounds of Table C1, or a pharma- ceutically acceptable salt thereof.

[0334] [Table C1] TIFF2024502755000083.tif184170TIFF2024502755000084.tif202170TIFF2024502755000085.t if174170TIFF2024502755000086.tif179170TIFF2024502755000087.tif161170TIFF20245027550 00088.tif201170TIFF2024502755000089.tif194170TIFF2024502755000090.tif194170TIFF202 4502755000091.tif157170TIFF2024502755000092.tif201170TIFF2024502755000093.tif101170

[0335] STING inhibitory nucleic acid In some embodiments of any of the methods described herein, the STING antagonist is an inhibitory nucleic acid. In some embodiments, the inhibitory nucleic acid is a short interfering RNA, an antisense nucleic acid, a cyclic dinucleotide, or a ribozyme.

[0336] Examples of these different oligonucleotide aspects are described below. Any of the examples of inhibitory nucleic acids that are STING antagonists can reduce the expression of STING mRNA in mammalian cells (e.g., human cells). Any of the inhibitory nucleic acids described herein can be synthesized in vitro.

[0337] Inhibitory nucleic acids capable of reducing the expression of STING mRNA in mammalian cells include antisense nucleic acid molecules, i.e., nucleic acid molecules whose nucleotide sequence is complementary to all or part of STING mRNA (e.g., complementary to all or part of any one of SEQ ID NOs: 1, 3, 5, or 7).

[0338] The antisense nucleic acid molecule can be complementary to all or part of a noncoding region of the coding strand of a nucleotide sequence encoding a STING protein. Noncoding regions (5' and 3' untranslated regions) are the 5' and 3' sequences that flank the coding region in a gene and are not translated into amino acids.

[0339] Based on the sequences disclosed herein, one skilled in the art can easily select and synthesize any of several antisense nucleic acids suitable for targeting the nucleic acid encoding the STING protein described herein.Antisense nucleic acids targeting the nucleic acid encoding the STING protein can be designed using software available on the Integrated DNA Technologies website.

[0340] Examples of modified nucleotides that can be used to generate antisense nucleic acids include 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxymethyl)uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carbazolyl, 5-methyl-2-thiouridine ... 5-methyl-2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methyl ester, uracil-5-oxyacetic acid (v), 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl)uracil, (acp3)w, and 2,6-diaminopurine. Alternatively, antisense nucleic acids can be produced biologically using an expression vector into which a nucleic acid has been subcloned in an antisense orientation (i.e., RNA transcribed from the inserted nucleic acid is in an antisense orientation to the target nucleic acid of interest).

[0341] The antisense nucleic acid molecules described herein can be prepared in vitro and administered to a subject, for example, a human subject. Alternatively, antisense nucleic acid molecules can be made in situ to hybridize or bind to cellular mRNA and / or genomic DNA encoding STING protein, thereby inhibiting expression, for example, by inhibiting transcription and / or translation. Hybridization can be by conventional nucleotide complementarity to form a stable duplex, or through specific interactions in the major groove of the double helix, for example, in the case of antisense nucleic acid molecules that bind to DNA duplexes. Antisense nucleic acid molecules can be delivered to mammalian cells using vectors (e.g., adenovirus vectors, lentiviruses, or retroviruses).

[0342] The antisense nucleic acid can be an α-anomeric nucleic acid molecule. The α-anomeric nucleic acid molecule forms specific double-stranded hybrids with complementary RNA in which the strands run parallel to each other, in contrast to the usual β units (Gaultier et al., Nucleic Acids Res. 15:6625-6641, 1987). The antisense nucleic acid can also comprise chimeric RNA-DNA analogs (Inoue et al., FEBS Lett. 215:327-330, 1987) or 2'-O-methyl ribonucleotides (Inoue et al., Nucleic Acids Res. 15:6131-6148, 1987).

[0343] Another example of an inhibitory nucleic acid is a ribozyme with specificity for a nucleic acid encoding STING mRNA, for example, any one of SEQ ID NOs: 1, 3, 5, or 7. Ribozymes are catalytic RNA molecules with ribonuclease activity that can cleave single-stranded nucleic acids, such as mRNAs, to which they have a complementary region. Thus, ribozymes (e.g., hammerhead ribozymes (described in Haselhoff and Gerlach, Nature 334:585-591, 1988)) can be used to catalytically cleave mRNA transcripts, thereby inhibiting the translation of proteins encoded by the mRNA. STING mRNA can be used to select catalytic RNAs with specific ribonuclease activity from a pool of RNA molecules. See, for example, Bartel et al., Science 261:1411-1418, 1993.

[0344] Alternatively, ribozymes with specificity for the STING mRNA sequence are disclosed herein. For example, Tetrahymena L-19 IVS RNA derivatives can be constructed in which the active site nucleotide sequence is complementary to the nucleotide sequence to be cleaved in STING mRNA (see, e.g., U.S. Patent Nos. 4,987,071 and 5,116,742).

[0345] Inhibitory nucleic acid can also be a nucleic acid molecule that forms a triple helix structure.For example, it can inhibit the expression of STING polypeptide by targeting the nucleotide sequence that is complementary to the regulatory region of the gene that codes for STING polypeptide (e.g., promoter and / or enhancer, e.g., sequence at least 1 kb, 2 kb, 3 kb, 4 kb, or 5 kb upstream of the transcription start state), thereby forming a triple helix structure that prevents the transcription of the gene in target cells.See generally Maher, Bioassays 14(12):807-15, 1992; Helene, Anticancer Drug Des. 6(6):569-84, 1991; and Helene, Ann. NY Acad. Sci. 660:27-36, 1992.

[0346] In various embodiments, inhibitory nucleic acids can be modified at the sugar moiety, base moiety, or phosphate backbone to improve, for example, the solubility, stability, or hybridization of the molecule. For example, the deoxyribose phosphate backbone of nucleic acids can be modified to create peptide nucleic acids (see, for example, Hyrup et al., Bioorganic Medicinal Chem. 4(1):5-23, 1996). Peptide nucleic acids (PNAs) are nucleic acid mimics, e.g., DNA mimics, in which the deoxyribose phosphate backbone is replaced with a pseudopeptide backbone and only four natural nucleic acid bases are retained. The neutral backbone of PNA allows specific hybridization to RNA and DNA under low ionic strength conditions. PNA oligomers can be synthesized using standard solid-phase peptide synthesis protocols (see, for example, Perry-O'Keefe et al., Proc. Natl. Acad. Sci. USA 93:14670-675, 1996). PNAs can be used as antisense or antigene agents for sequence-specific modulation of gene expression, eg, by inducing transcription or translation arrest or inhibiting replication.

[0347] cGAS inhibitors In any of the methods described herein, the cGAS inhibitor can be any cGAS inhibitor described herein (e.g., any compound described in this section). In any of the methods described herein, the cGAS inhibitor has an IC for cGAS of about 1 nM to about 10 μM. 50 has.

[0348] In one aspect, the cGAS inhibitor is a compound selected from the group consisting of the compounds of Table C2 and pharma- ceutically acceptable salts thereof.

[0349] [Table C2]

[0350] In some embodiments, the cGAS inhibitor is selected from the compounds disclosed in U.S. Provisional Application No. 62 / 355,403, filed June 28, 2016, which is incorporated by reference in its entirety.

[0351] In some embodiments, the cGAS inhibitor is selected from the compounds disclosed in U.S. Provisional Application No. 62 / 318,435, filed April 5, 2016, which is incorporated by reference in its entirety.

[0352] In some embodiments, the cGAS inhibitor is selected from the compounds disclosed in U.S. Patent Application Publication No. 2018 / 0230115 A1, published August 16, 2018, which is incorporated by reference in its entirety.

[0353] In some embodiments, the cGAS inhibitor is selected from the compounds disclosed in Vincent, J. et al. (2017) Nat. Commun. 8(1):750, which is incorporated by reference in its entirety.

[0354] In some embodiments, the cGAS inhibitor is selected from the compounds disclosed in Hall, J. et al. (2017) PLOS ONE 12(9):e184843, which is incorporated by reference in its entirety.

[0355] In some embodiments, the cGAS inhibitor is selected from the compounds disclosed in Wang, M. et al. (2018) Future Med. Chem. 10(11):1301-17, which is incorporated by reference in its entirety.

[0356] In some embodiments, the cGAS inhibitor is selected from the compounds disclosed in U.S. Provisional Application No. 62 / 559,482, filed September 15, 2017, which is incorporated by reference in its entirety.

[0357] In some embodiments, the cGAS inhibitor is selected from the compounds disclosed in U.S. Provisional Application No. 62 / 633,248, filed February 21, 2018, which is incorporated by reference in its entirety.

[0358] In some embodiments, the cGAS inhibitor is selected from the compounds disclosed in U.S. Provisional Application No. 62 / 687,769, filed June 20, 2018, which is incorporated by reference in its entirety.

[0359] Pharmaceutical Compositions In some embodiments, a STING antagonist (e.g., any STING antagonist described herein or known in the art) is administered as a pharmaceutical composition comprising the chemical entity, one or more pharma- ceutically acceptable excipients, and optionally one or more additional therapeutic agents described herein.

[0360] In some embodiments, the STING antagonist can be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tween, poloxamer, or other similar polymer delivery matrices, serum proteins such as human serum albumin, buffer substances such as phosphates, Tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, salts or electrolytes such as zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block copolymers, and wool fat. Additionally, chemically modified derivatives such as cyclodextrins, such as α-, β-, and γ-cyclodextrin, or hydroxyalkyl cyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrin, or other solubilizing derivatives, can be used to improve delivery of the STING antagonists described herein. Dosage forms or compositions can be prepared that contain the STING antagonists described herein in the range of 0.005%-100%, with the remainder consisting of non-toxic excipients. Contemplated compositions may contain 0.001%-100%, in one embodiment 0.1-95%, in another embodiment 75-85%, and in a further embodiment 20-80% STING antagonist. Actual methods for preparing these dosage forms will be known or apparent to those of skill in the art. For example, see Remington: The Science and Practice of Pharmacy, 22 nd Edition (Pharmaceutical Press, London, UK. 2012).

[0361] Route of Administration and Composition Components In some embodiments, a STING antagonist (e.g., any of the exemplary STING antagonists described herein or known in the art), or pharmaceutical composition thereof, can be administered to a subject in need thereof by any acceptable route of administration, including buccal, dermal, intracervical, endosinusial, intratracheal, intraintestinal, epidural, intrainterstitial, intraperitoneal, intraarterial, intrabronchial, intravesical, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intraantral, intravenous ... These include, but are not limited to, intraasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intraductal, intratumoral, intrauterine, intravascular, intravenous, intranasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral, ​​and intravaginal. In certain embodiments, the preferred route of administration is parenteral (e.g., intratumoral).

[0362] Compositions can be formulated for parenteral administration, for example, for injection by intravenous, intramuscular, subcutaneous or even intraperitoneal route.Generally, these compositions can be prepared as injections, as liquid solutions or suspensions, and can also be prepared in solid form suitable for use in preparing liquid solutions or suspensions before injection, or can be emulsified.In light of this disclosure, the preparation of these formulations will be clear to those skilled in the art.

[0363] The pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions; formulations containing sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for extemporaneous preparation of sterile injectable solutions or dispersions.In any case, the form must be sterile and fluid to the extent that it can be easily injected.In addition, the form must be stable under the conditions of manufacture and storage, and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.

[0364] The carrier can also be a solvent or dispersion medium, including, for example, water, ethanol, polyol (such as glycerin, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it is preferable to include an isotonic agent, for example, sugar or sodium chloride. Prolonged absorption of the injectable composition can be achieved by the use of an absorption-delaying agent in the composition, for example, aluminum monostearate and gelatin.

[0365] Sterile injectable solution is prepared by incorporating the required amount of STING antagonist in a suitable solvent together with various other components as listed above as necessary, and then performing filtration sterilization.Generally, dispersion is prepared by incorporating various sterilized active ingredients into a sterile medium that contains a basic dispersion medium and other necessary components listed above.For the preparation of sterile injectable solution, the preferred preparation method is vacuum drying and freeze-drying technology, which produces a powder of active ingredient and any additional desired ingredients from the solution that has already been sterilized and filtered.

[0366] Intratumoral injections are described, for example, in Lammers, et al., "Effect of Intratumoral Injection on the Biodistribution and the Therapeutic Potential of HPMA Copolymer-Based Drug Delivery Systems" Neoplasia. 2006, 10, 788-795.

[0367] In certain embodiments, the STING antagonist or pharmaceutical composition thereof is suitable for local or topical administration to the digestive or gastrointestinal tract, such as rectal administration, including, but not limited to, enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, and enemas (e.g., retention enemas).

[0368] Pharmacologically acceptable excipients that may be used in rectal compositions as gels, creams, enemas, or rectal suppositories include cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (as in PEG ointment), glycerin, glycerinated gelatin, hydrogenated vegetable oils, poloxamer, mixtures of polyethylene glycols of various molecular weights and polyethylene glycol fatty acid esters, petrolatum, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxid These include, but are not limited to, one or more of SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p-oxybenzoate, sodium propyl p-oxybenzoate, diethylamine, carbomer, Carbopol, methyl oxybenzoate, macrogol cetostearyl ether, cocoyl caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methylsulfonylmethane (MSM), lactic acid, glycine, vitamins such as vitamins A and E, and potassium acetate.

[0369] In certain embodiments, suppositories can be prepared by mixing the STING antagonist with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or a suppository wax, which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum to release the active compound. In other embodiments, the composition for rectal administration is in the form of an enema.

[0370] In other embodiments, the STING antagonist or pharmaceutical composition thereof is suitable for local delivery to the digestive or gastrointestinal tract by oral administration (e.g., in a solid or liquid dosage form).

[0371] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the STING antagonist is mixed with one or more pharma- ceutically acceptable excipients, such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants, such as glycerin; d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarding agents, such as paraffin; f) absorption accelerators, such as quaternary ammonium compounds; g) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; h) absorbents, such as kaolin clay and bentonite clay; and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and combinations thereof. In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents. Solid compositions of a similar type may also be employed as fillers in soft- and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols.

[0372] In one embodiment, the composition is in the form of a unitary dosage form such as a pill or tablet, and thus the composition may contain, together with the STING antagonist, a diluent such as lactose, sucrose, dicalcium phosphate; a lubricant such as magnesium stearate; and a binder such as starch, gum arabic, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives. In another solid dosage form, a powder, marume, solution or suspension (e.g. in propylene carbonate, vegetable oil, PEG, poloxamer 124, or triglyceride) is enclosed in a capsule (gelatin or cellulose-based capsule). Unitary dosage forms in which one or more STING antagonists or additional active agents are physically separated are also envisioned, such as capsules with granules (or tablets in capsules) of each drug; bilayer tablets; bicompartment gel capsules, etc. Enteric-coated oral dosage forms or delayed release oral dosage forms are also envisioned.

[0373] Other physiologically acceptable compounds include wetting agents, emulsifying agents, dispersing agents, or preservatives that are particularly useful for preventing the growth or action of microorganisms. Various preservatives are well known and include, for example, phenol and ascorbic acid.

[0374] In certain embodiments, the excipients are sterile and generally free of undesirable materials. These compositions can be sterilized by conventional, well-known sterilization techniques. Sterility is not required for excipients of various oral dosage forms, such as tablets and capsules. USP / NF standards are usually sufficient.

[0375] In certain embodiments, the solid oral dosage form may further comprise one or more components that chemically and / or structurally adapt the composition for delivery of STING antagonist to the stomach or lower gastrointestinal tract; for example, the ascending colon and / or the transverse colon and / or the distal colon and / or the small intestine.Exemplary formulation techniques are described, for example, in Filipski, KJ, et al., Current Topics in Medicinal Chemistry, 2013, 13, 776-802, the entire contents of which are incorporated herein by reference.

[0376] Examples include technologies that target the upper gastrointestinal tract, such as the Accordion Pill (Intec Pharma), floating capsules, and materials capable of adhering to mucosal walls.

[0377] Other examples include technologies that target the lower gastrointestinal tract. Several enteric / pH-responsive coatings and excipients are available to target various regions in the intestinal tract. Typically, these materials are polymers designed to dissolve or erode at a specific pH range selected based on the gastrointestinal tract region where drug release is desired. These materials also function to protect acid-labile drugs from gastric juices or to limit exposure if the active ingredient may be irritating to the upper gastrointestinal tract (e.g., hydroxypropyl methylcellulose phthalate series, Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Eudragit series (methacrylic acid-methyl methacrylate copolymer), and Marcoat). Other technologies include dosage forms that respond to localized bacterial flora in the gastrointestinal tract, pressure-controlled colonic delivery capsules, and Pulsincap.

[0378] Ophthalmic compositions may include, but are not limited to, any one or more of the following: viscogens (e.g., carboxymethylcellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol); stabilizers (e.g., Pluronic (triblock copolymers), cyclodextrin); preservatives (e.g., benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (a stabilized oxychloro complex; Allergan, Inc.)).

[0379] Topical compositions can include ointments and creams. Ointments are semi-solid preparations that are usually based on petrolatum or other petroleum derivatives. Creams that contain STING antagonists are usually liquid or semi-solid emulsions, often oil-in-water or water-in-oil. Cream bases are usually washable with water and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase, sometimes called the "internal" phase, is generally composed of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol, and the aqueous phase usually, but not necessarily, exceeds the oil phase in terms of volume and generally contains a humectant. Generally, the emulsifier in a cream formulation is a non-ionic, anionic, cationic, or amphoteric surfactant. As with other carriers or vehicles, ointment bases should be inert, stable, non-irritating, and non-sensitizing.

[0380] In any of the above embodiments, the pharmaceutical compositions described herein may include one or more of the following: lipids, interbilayer cross-linked multilamellar vesicles, biodegradable poly(D,L-lactic-co-glycolic acid) [PLGA]-based or polyanhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.

[0381] Enema preparations In some embodiments, the enema formulation containing the STING antagonist is provided in a "ready to use" form.

[0382] In some embodiments, the enema formulation containing the STING antagonist is provided in one or more kits or packs. In certain embodiments, the kit or pack contains two or more separately contained / packaged components, e.g., two components, that when mixed together provide the desired formulation (e.g., as a suspension). In some of these embodiments, the two-component system includes a first component and a second component, where (i) the first component (e.g., contained in a sachet) contains a STING antagonist (as described elsewhere herein) and optionally one or more pharma- ceutically acceptable excipients (e.g., formulated together as a solid formulation, e.g., formulated together as a wet granulation solid formulation), and (ii) the second component (e.g., contained in a vial or bottle) contains one or more liquids and, optionally, one or more other pharma-ceutically acceptable excipients that together form a liquid carrier. Prior to use (e.g., immediately before use), the contents of (i) and (ii) are combined to form the desired enema formulation, e.g., as a suspension. In other embodiments, components (i) and (ii) are each provided in their own separate kit or pack.

[0383] In some embodiments, each of the one or more liquids is water or a physiologically acceptable solvent, or a mixture of water and one or more physiologically acceptable solvents.Typical solvents include, but are not limited to, glycerol, ethylene glycol, propylene glycol, polyethylene glycol, and polypropylene glycol.In certain embodiments, each of the one or more liquids is water.In other embodiments, each of the one or more liquids is oil, for example, natural oils and / or synthetic oils that are commonly used in pharmaceutical preparations.

[0384] Further pharmaceutical excipients and carriers that can be used in the pharmaceutical formulations described herein are listed in various handbooks (e.g. DE Bugay and WP Findlay (Eds) Pharmaceutical excipients (Marcel Dekker, New York, 1999), EM Hoepfner, A. Reng and PC Schmidt (Eds) Fiedler Encyclopedia of Excipients for Pharmaceuticals, Cosmetics and Related Areas (Edition Cantor, Munich, 2002) and HP Fielder (Ed) Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete (Edition Cantor Aulendorf, 1989)).

[0385] In some embodiments, the one or more pharma- ceutically acceptable excipients may each be independently selected from a thickening agent, a viscosity enhancing agent, a bulking agent, a mucoadhesive agent, a penetration enhancer, a buffer, a preservative, a diluent, a binder, a lubricant, a glidant, a disintegrant, a filler, a solubilizing agent, a pH adjusting agent, a preservative, a stabilizer, an antioxidant, a wetting agent or an emulsifying agent, a suspending agent, a pigment, a coloring agent, an isotonicity agent, a chelating agent, an emulsifying agent, and a diagnostic agent.

[0386] In certain embodiments, the one or more pharma- ceutically acceptable excipients may each be independently selected from a thickening agent, a viscosity enhancing agent, a mucoadhesive agent, a buffering agent, a preservative, a diluent, a binder, a lubricant, a glidant, a disintegrant, and a filler.

[0387] In certain embodiments, the one or more pharma- ceutical acceptable excipients may each be independently selected from a thickening agent, a viscosity enhancing agent, a bulking agent, a mucoadhesive agent, a buffering agent, a preservative, and a bulking agent.

[0388] In certain embodiments, the one or more pharma- ceutically acceptable excipients may each be independently selected from a diluent, a binder, a lubricant, a glidant, and a disintegrant.

[0389] Examples of thickening agents, viscosity enhancers, and mucoadhesives include gums such as xanthan gum, guar gum, locust bean gum, tragacanth gum, karaya gum, ghatti gum, prickly pear gum, psyllium seed gum, and gum arabic; poly(carboxylic acid-containing) based polymers such as poly(acrylic acid, maleic acid, itaconic acid, citraconic acid, hydroxyethyl methacrylic acid, or methacrylic acid) having strong hydrogen bonding groups, or derivatives thereof, such as salts and esters; cellulose derivatives such as methylcellulose, ethylcellulose, methylethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylethylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, or cellulose esters or cellulose ethers or derivatives or salts thereof; clays such as montmorillonite clays, e.g., veegum, attapulgite clays; Examples of suitable polysaccharides include, but are not limited to, polysaccharides such as dextran, pectin, amylopectin, agar, mannan, or polygalactonic acid, or starches such as hydroxypropyl starch or carboxymethyl starch; polypeptides such as casein, gluten, gelatin, fibrin glue; chitosans such as lactate or glutamate or carboxymethyl chitin; glycosaminoglycans such as hyaluronic acid; metal or water-soluble salts of alginic acid such as sodium or magnesium alginate; scleroglucan; adhesives containing bismuth oxide or aluminum oxide; atelocollagen; polyvinyl polymers such as carboxyvinyl polymers; polyvinylpyrrolidone (povidone); polyvinyl alcohol; polyvinyl acetate, polyvinyl methyl ether, polyvinyl chloride, polyvinylidene chloride, and the like; polycarboxylated vinyl polymers such as the polyacrylic acids mentioned above; polysiloxanes; polyethers; polyethylene oxides and glycols; polyalkoxy and polyacrylamides and derivatives and salts thereof.Preferred examples include cellulose derivatives, such as methylcellulose, ethylcellulose, methylethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylethylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, or cellulose esters or cellulose ethers or derivatives or salts thereof (e.g., methylcellulose); and polyvinyl polymers, such as polyvinylpyrrolidone (povidone).

[0390] Examples of preservatives include, but are not limited to, benzalkonium chloride, benzoxonium chloride, benzethonium chloride, cetrimide, sepazonium chloride, cetylpyridinium chloride, domiphen bromide (Bradosol®), thiomersal, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric borate, methylparaben, propylparaben, chlorobutanol, benzyl alcohol, phenylethyl alcohol, chlorhexidine, polyhexamethylene biguanide, sodium perborate, imidazolidinyl urea, sorbic acid, Purite®, Polyquart®, and sodium perborate tetrahydrate.

[0391] In certain embodiments, the preservative is a paraben or a pharma- ceutically acceptable salt thereof. In some embodiments, the paraben is an alkyl-substituted 4-hydroxybenzoate or a pharma- ceutically acceptable salt or ester thereof. In certain embodiments, the alkyl is a C1-C4 alkyl. In certain embodiments, the preservative is methyl 4-hydroxybenzoate (methylparaben) or a pharma- ceutically acceptable salt or ester thereof, propyl 4-hydroxybenzoate (propylparaben) or a pharma- ceutically acceptable salt or ester thereof, or a combination thereof.

[0392] Examples of buffers include, but are not limited to, phosphate buffer systems (sodium dihydrogen phosphate dihydrate, sodium phosphate disodium dodecahydrate, sodium phosphate dibasic, sodium phosphate monobasic anhydrous), bicarbonate buffer systems, and hydrogen sulfate buffer systems.

[0393] Examples of disintegrants include, but are not limited to, carmellose calcium, low-substituted hydroxypropylcellulose (L-HPC), carmellose, croscarmellose sodium, partially pregelatinized starch, dry starch, sodium carboxymethyl starch, crospovidone, polysorbate 80 (polyoxyethylene sorbitan oleate), starch, sodium starch glycolate, hydroxypropylcellulose, pregelatinized starch, clay, cellulose, arginine, gum, or cross-linked polymers such as cross-linked PVP (Polyplasdone XL from GAF Chemical Corp). In certain embodiments, the disintegrant is crospovidone.

[0394] Examples of glidants and lubricants (aggregation inhibitors) include, but are not limited to, talc, magnesium stearate, calcium stearate, colloidal silica, stearic acid, hydrous silicon dioxide, synthetic magnesium silicate, finely divided silicon oxide, starch, sodium lauryl sulfate, boric acid, magnesium oxide, wax, hydrogenated oil, polyethylene glycol, sodium benzoate, stearic acid, glycerol behenate, polyethylene glycol, and mineral oil. In certain embodiments, the glidant / lubricant is magnesium stearate, talc, and / or colloidal silica; e.g., magnesium stearate and / or talc.

[0395] Examples of diluents, also referred to as "fillers" or "bulking agents," include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose (e.g., lactose monohydrate), sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starch, pregelatinized starch, silicon dioxide, titanium dioxide, magnesium aluminum silicate, and powdered sugar. In certain embodiments, the diluent is lactose (e.g., lactose monohydrate).

[0396] Examples of binders include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dextrose, lactose, and sorbitol), polyethylene glycol, waxes, natural and synthetic gums such as gum arabic, tragacanth, sodium alginate, celluloses including hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, and veegum, and synthetic polymers such as acrylic and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid / polymethacrylic acid, and polyvinylpyrrolidone (povidone). In certain embodiments, the binder is polyvinylpyrrolidone (povidone).

[0397] In some embodiments, an enema formulation comprising a STING antagonist comprises water and one or more (e.g., all) of the following excipients: one or more (e.g., one, two, or three) thickening agents, viscosity enhancing agents, binders, and / or mucoadhesives (e.g., cellulose or a cellulose ester or ether, or a derivative or salt thereof (e.g., methylcellulose)); and a polyvinyl polymer, such as polyvinylpyrrolidone (povidone); one or more (e.g., one or two; e.g., two) preservatives, such as methyl 4-hydroxybenzoate (methylparaben) or a pharma- ceutically acceptable salt or ester thereof, propyl 4-hydroxybenzoate (propylparaben) or a pharma- ceutically acceptable salt or ester thereof, or a combination thereof; one or more (e.g., one or two; e.g., two) buffering agents, such as a phosphate buffer system (e.g., sodium dihydrogen phosphate dihydrate, disodium phosphate dodecahydrate); one or more (e.g., one or two, e.g., two) glidants and / or lubricants, such as magnesium stearate and / or talc; one or more (e.g., one or two; e.g., one) disintegrants, such as crospovidone; and one or more (eg, one or two; eg, one) diluents, such as lactose (eg, lactose monohydrate).

[0398] In certain embodiments, the enema formulation comprising STING antagonist comprises water, methylcellulose, povidone, methylparaben, propylparaben, sodium dihydrogen phosphate dihydrate, disodium phosphate dodecahydrate, crospovidone, lactose monohydrate, magnesium stearate, and talc.In certain embodiments, the enema formulation comprising STING antagonist is provided as one or more kits or packs.In certain embodiments, the kit or pack comprises two separately contained / packaged components that, when mixed together, provide the desired formulation (e.g., as a suspension). In some of these embodiments, the two-component system comprises a first component and a second component, where (i) the first component (e.g., contained in a sachet) comprises a STING antagonist (as described elsewhere herein) and one or more pharma- ceutically acceptable excipients (e.g., formulated together as a solid formulation, e.g., formulated together as a wet granulated solid formulation), and (ii) the second component (e.g., contained in a vial or bottle) comprises one or more liquids and one or more other pharma- ceutically acceptable excipients that together form a liquid carrier. In other embodiments, components (i) and (ii) are each provided in their own separate kit or pack.

[0399] In some of these embodiments, component (i) comprises a STING antagonist (e.g., a compound of any one of Formulas I-XXIV (e.g., Formulas XI-XV) or Formulas M1-M6 (e.g., Formulas M3-M6) or a compound set forth in Table C1, or a pharma- ceutically acceptable salt and / or hydrate and / or co-crystal thereof), and one or more (e.g., all) of the following excipients: (a) one or more (e.g., one) binders (e.g., a polyvinyl polymer, such as polyvinylpyrrolidone (povidone)); (b) one or more (e.g., one or two, e.g., two) glidants and / or lubricants, such as magnesium stearate and / or talc; (c) one or more (e.g., one or two; e.g., one) disintegrants, such as crospovidone; and (d) one or more (e.g., one or two; e.g., one) diluents, such as lactose (e.g., lactose monohydrate).

[0400] In certain embodiments, component (i) comprises about 40 weight percent to about 80 weight percent (e.g., about 50 weight percent to about 70 weight percent, about 55 weight percent to about 70 weight percent; about 60 weight percent to about 65 weight percent; e.g., about 62.1 weight percent) of a STING antagonist (e.g., a compound of any one of Formulas I-XXIV (e.g., Formulas XI-XV) or Formulas M1-M6 (e.g., Formulas M3-M6), or a compound set forth in Table C1, or a pharma- ceutically acceptable salt and / or hydrate and / or co-crystal thereof).

[0401] In certain embodiments, component (i) comprises about 0.5 weight percent to about 5 weight percent (e.g., about 1.5 weight percent to about 4.5 weight percent, about 2 weight percent to about 3.5 weight percent; e.g., about 2.76 weight percent) of a binder (e.g., povidone).

[0402] In certain embodiments, component (i) comprises about 0.5 weight percent to about 5 weight percent (e.g., about 0.5 weight percent to about 3 weight percent, about 1 weight percent to about 3 weight percent; about 2 weight percent, e.g., about 1.9 weight percent) of a disintegrant (e.g., crospovidone).

[0403] In certain embodiments, component (i) comprises about 10 weight percent to about 50 weight percent (e.g., about 20 weight percent to about 40 weight percent, about 25 weight percent to about 35 weight percent; e.g., about 31.03 weight percent) of a diluent (e.g., lactose, e.g., lactose monohydrate).

[0404] In certain embodiments, component (i) comprises from about 0.05 weight percent to about 5 weight percent (eg, from about 0.05 weight percent to about 3 weight percent) of a glidant and / or lubricant.

[0405] In certain embodiments (e.g., when component (i) includes one or more lubricants, e.g., magnesium stearate), component (i) includes from about 0.05 weight percent to about 1 weight percent (e.g., from about 0.05 weight percent to about 1 weight percent; from about 0.1 weight percent to about 1 weight percent; from about 0.1 weight percent to about 0.5 weight percent; e.g., about 0.27 weight percent) of the lubricant (e.g., magnesium stearate).

[0406] In certain embodiments (when component (i) includes one or more lubricants, e.g., talc), component (i) includes from about 0.5 weight percent to about 5 weight percent (e.g., from about 0.5 weight percent to about 3 weight percent, from about 1 weight percent to about 3 weight percent; from about 1.5 weight percent to about 2.5 weight percent; from about 1.8 weight percent to about 2.2 weight percent; about 1.93 weight percent) of the lubricant (e.g., talc).

[0407] In some of these embodiments, each of (a), (b), (c), and (d) above is present.

[0408] In certain embodiments, component (i) comprises the ingredients and amounts shown in Table A.

[0409] [Table A] TIFF2024502755000096.tif44153

[0410] In certain embodiments, component (i) comprises the ingredients and amounts shown in Table B.

[0411] [Table B]

[0412] In certain embodiments, component (i) is formulated as a wet granulation solid formulation. In some of these embodiments, the components of the internal phase (STING antagonist, disintegrant, and diluent) are combined and mixed in a high shear granulator. A binder (e.g., povidone) is dissolved in water to form a granulation solution. This solution is added to the internal phase mixture to generate granules. Without wishing to be bound by theory, it is believed that granulation is promoted by the interaction of the polymeric binder with the materials of the internal phase. When the granules are formed and dried, an external phase (e.g., one or more lubricants - not an inherent component of the dried granules) is added to the dried granules. It is believed that lubrication of the granules is important for the flowability of the granules, especially in packaging.

[0413] In certain of the above embodiments, component (ii) includes water and one or more (e.g., all) of the following excipients: (a') one or more (e.g., one, two; e.g., two) thickening agents, viscosity enhancing agents, binders, and / or mucoadhesives (e.g., cellulose or a cellulose ester or ether, or a derivative or salt thereof (e.g., methylcellulose)); and a polyvinyl polymer, e.g., polyvinylpyrrolidone (povidone); (b') one or more (e.g., one or two; e.g., two) preservatives, such as methyl 4-hydroxybenzoate (methylparaben) or a pharma- ceutically acceptable salt or ester thereof, propyl 4-hydroxybenzoate (propylparaben) or a pharma- ceutically acceptable salt or ester thereof, or a combination thereof; and (c') one or more (e.g., one or two; e.g., two) buffering agents, such as a phosphate buffer system (e.g., sodium dihydrogen phosphate dihydrate, disodium phosphate dodecahydrate).

[0414] In certain of the above embodiments, component (ii) includes water and one or more (e.g., all) of the following excipients: (a'') a first thickening, viscosity enhancing, binding, and / or mucoadhesive agent (e.g., cellulose or a cellulose ester or ether, or a derivative or salt thereof (e.g., methylcellulose)); (a''') a second thickening agent, viscosity enhancing agent, binder, and / or mucoadhesive agent (e.g., a polyvinyl polymer, e.g., polyvinylpyrrolidone (povidone)); (b'') a first preservative, such as a paraben, such as propyl 4-hydroxybenzoate (propylparaben), or a pharma- ceutically acceptable salt or ester thereof; (b'') a second preservative, such as a paraben, e.g., methyl 4-hydroxybenzoate (methylparaben), or a pharma- ceutically acceptable salt or ester thereof; (c'') a first buffer, such as a phosphate buffer system (e.g., disodium phosphate dodecahydrate); (c''') a second buffer, such as a phosphate buffer system (e.g., sodium dihydrogen phosphate dihydrate).

[0415] In certain embodiments, component (ii) comprises from about 0.05 weight percent to about 5 weight percent (e.g., from about 0.05 weight percent to about 3 weight percent, from about 0.1 weight percent to about 3 weight percent; e.g., about 1.4 weight percent) of (a″).

[0416] In certain embodiments, component (ii) comprises from about 0.05 weight percent to about 5 weight percent (e.g., from about 0.05 weight percent to about 3 weight percent, from about 0.1 weight percent to about 2 weight percent; e.g., about 1.0 weight percent) of (a''').

[0417] In certain embodiments, component (ii) comprises from about 0.005 weight percent to about 0.1 weight percent (eg, from about 0.005 weight percent to about 0.05 weight percent; e.g., about 0.02 weight percent) of (b'').

[0418] In certain embodiments, component (ii) comprises from about 0.05 weight percent to about 1 weight percent (eg, from about 0.05 weight percent to about 0.5 weight percent; e.g., about 0.20 weight percent) of (b''').

[0419] In certain embodiments, component (ii) comprises from about 0.05 weight percent to about 1 weight percent (eg, from about 0.05 weight percent to about 0.5 weight percent; e.g., about 0.15 weight percent) of (c'').

[0420] In certain embodiments, component (ii) comprises from about 0.005 weight percent to about 0.5 weight percent (eg, from about 0.005 weight percent to about 0.3 weight percent; e.g., about 0.15 weight percent) of (c''').

[0421] In some of these embodiments, each of (a'') through (c'') is present.

[0422] In certain embodiments, component (ii) comprises water (up to 100%) and the ingredients and amounts shown in Table C.

[0423] [Table C]

[0424] In certain embodiments, component (ii) comprises water (up to 100%) and the ingredients and amounts shown in Table D.

[0425] [Table D]

[0426] Generally, "ready-to-use" enemas are provided as "single-use" sealed disposable plastic or glass containers. Enemas formed of polymeric materials are preferably sufficiently flexible to facilitate use by unassisted patients. Typical plastic containers may be made of polyethylene. These containers may include a tip for direct introduction into the rectum. These containers may also include a tube between the container and the tip. The tip is preferably provided with a protective shield that is removed prior to use. Optionally, the tip has a lubricant to improve patient compliance.

[0427] In some embodiments, the enema preparation (e.g., suspension) is prepared in a separate container and then poured into a bottle for delivery. In certain embodiments, the bottle is a plastic bottle (e.g., flexible enough to allow delivery by squeezing the bottle), which can be a polyethylene bottle (e.g., white). In some embodiments, the bottle is a single-chambered bottle that contains a suspension or solution. In other embodiments, the bottle is a multi-chambered bottle, in which each compartment contains a separate mixture or solution. In still other embodiments, the bottle can further include a tip or rectal cannula for direct introduction into the rectum. In some embodiments, the enema preparation can be delivered with an apparatus that includes a plastic bottle, a frangible capsule, a rectal cannula, and a single-flow pack.

[0428] Dosage Dosage may vary depending on the patient's requirements, the severity of the condition being treated, and the specific compound being used.The appropriate dosage for a particular situation can be determined by those skilled in the medical field.The total daily dosage can be divided and administered in several portions throughout the day, or administered by means of continuous delivery.

[0429] In some embodiments, the STING antagonist is administered at a dosage of about 0.001 mg / kg to about 500 mg / kg.

[0430] In some embodiments, the enema formulation contains from about 0.5 mg to about 2500 mg of the chemical entity in from about 1 mL to about 3000 mL of liquid carrier.

[0431] Regimen The above dosages can be administered daily (e.g., as one or two or more divided doses) or non-daily (e.g., every other day, every second day, every third day, weekly, twice every few weeks, biweekly, monthly).

[0432] In some embodiments, the administration period of the STING antagonist is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In further embodiments, the period of time during which administration is suspended is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In one embodiment, the STING antagonist is administered to the individual for one period of time, followed by another period of time. In another embodiment, the STING antagonist is administered for a first period of time, and a second period of time following the first period of time, administration is suspended during the second period of time, followed by administration of the STING antagonist for a third period of time, followed by administration being suspended for a fourth period of time following the third period of time. In one aspect of this embodiment, the administration period of STING antagonist is repeated followed by a period during which administration is discontinued for a defined or indefinite period. In further embodiments, the administration period is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In further embodiments, administration is discontinued for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.

[0433] kit Also provided herein are kits comprising one or more (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16, 18, or 20) of any of the pharmaceutical compositions described herein. In some embodiments, the kits may include instructions for performing any of the methods described herein. In some embodiments, the kits may include at least one dose of any of the compositions (e.g., pharmaceutical compositions) described herein. In some embodiments, the kits may provide a syringe for administering any of the pharmaceutical compositions described herein. The kits described herein are not so limited, and other variations will be apparent to one of skill in the art. EXAMPLES

[0434] Example 1 Correlation between TREX1 allele copy number and cancer survival The first experiment was performed on samples from human subjects with renal cell carcinoma. TREX1 allele copy number and type 1 interferon-inducible gene expression were determined in each sample. Figure 1 shows that renal cell carcinoma subjects with reduced TREX1 allele copy number have increased type 1 interferon-inducible gene expression. Figures 2 and 3 show that renal cell carcinoma patients with reduced TREX1 allele copy number (with deleted TREX1) have reduced survival probability compared to subjects with increased TREX1 allele copy number (with diploid or amplified TREX1). TREX1 is deleted in up to 50% of renal cell carcinomas, which correlates with reduced survival.

[0435] 4A and 4B are graphs showing the correlation between TREX1 allele copy number and STING-dependent interferon-1 activation gene expression in samples from subjects with renal cell carcinoma. The data show that a decrease in TREX1 allele copy number correlates with an increase in STING-dependent interferon-1 activation gene expression in renal cell carcinoma subjects.

[0436] A further set of experiments was performed to compare TREX1 allele copy number or TREX1 protein expression in samples from subjects with uveal melanoma or osteosarcoma with survival rates over time, respectively. The data in Figure 5 show that patients with uveal melanoma with a decreased allele copy number of TREX1 (hypodiploid) have a decreased survival probability over time compared to patients with an increased allele copy number of TREX1 (diploid). The data in Figure 6 show that patients with osteosarcoma with a decreased protein level of TREX1 have a decreased survival probability over time compared to patients with an increased protein level of TREX1.

[0437] Other Aspects Although the present invention has been described in connection with its detailed description, it should be understood that the foregoing description is intended to illustrate, and not to limit, the scope of the invention as defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

[0438] Sequence Appendix Human STING cDNA, variant 1 (SEQ ID NO: 1) TIFF2024502755000100.tif106153

[0439] Human STING protein, variant 1 (SEQ ID NO: 2) TIFF2024502755000101.tif33153

[0440] Human STING cDNA, variant 2 (SEQ ID NO: 3) TIFF2024502755000102.tif82153

[0441] Human STING protein, variant 2 (SEQ ID NO: 4) TIFF2024502755000103.tif28153

[0442] Human STING cDNA, variant 3 precursor (SEQ ID NO: 5) TIFF2024502755000104.tif72153

[0443] Human STING protein, variant 3 precursor (SEQ ID NO: 6) TIFF2024502755000105.tif24152

[0444] Human STING cDNA, variant 3 mature sequence (SEQ ID NO: 7) TIFF2024502755000106.tif72153

[0445] Human STING protein, variant 3 mature sequence (SEQ ID NO: 8) TIFF2024502755000107.tif24152

[0446] Human TREX1 cDNA sequence, variant 1 (SEQ...

Claims

1. The following steps: (a) Compared to a reference level, (I) (i) a decrease in the level and / or activity of TREX1, and (ii) Increased activity of the cGAS / STING signaling pathway and / or (II) an increase in the level of cGAMP in a serum sample or a tumor sample obtained from the subject; identifying a subject having (b) administering to the identified subject a treatment comprising a therapeutically effective amount of a STING antagonist, or a pharma- ceutically acceptable salt, solvate, or cocrystal thereof; the STING antagonist is a compound of any one of Formulas I-XXIV or Formulas M1-M6, or a compound shown in Table C1; A method of treating a subject in need thereof, comprising:

16. A composition for use in a method for treating cancer, comprising administering to a patient a therapeutically effective amount of a STING antagonist, or a pharma- ceutically acceptable salt, solvate, or cocrystal thereof.

2. The following steps: Compared to the reference level, (I) (i) a decrease in the level and / or activity of TREX1, and (ii) Increased activity of the cGAS / STING signaling pathway and / or (II) an increase in the level of cGAMP in a serum sample or a tumor sample obtained from the subject; administering to a subject identified as having a treatment comprising a therapeutically effective amount of a STING antagonist, or a pharma- ceutically acceptable salt, solvate, or cocrystal thereof; the STING antagonist is a compound of any one of Formulas I-XXIV or Formulas M1-M6, or a compound shown in Table C1; A method of treating a subject in need thereof, comprising:

16. A composition for use in a method for treating cancer, comprising administering to a patient a therapeutically effective amount of a STING antagonist, or a pharma- ceutically acceptable salt, solvate, or cocrystal thereof.

3. The following steps: (a) Compared to a reference level, (I) (i) a decrease in the level and / or activity of TREX1, and (ii) Increased activity of the cGAS / STING signaling pathway and / or (II) an increase in the level of cGAMP in a serum sample or a tumor sample obtained from the subject; identifying a subject having (b) selecting, for the identified subject, a treatment comprising a therapeutically effective amount of a STING antagonist, or a pharma- ceutically acceptable salt, solvate, or cocrystal thereof; the STING antagonist is a compound of any one of Formulas I-XXIV or Formulas M1-M6, or a compound shown in Table C1; A method for selecting a treatment for a subject in need thereof, comprising: A composition for a treatment selected by the method of any one of claims 1 to 4, wherein the composition comprises a STING antagonist, or a pharma- ceutically acceptable salt, solvate, or cocrystal thereof.

4. The following steps: Compared to the reference level, (I) (i) a decrease in the level and / or activity of TREX1, and (ii) Increased activity of the cGAS / STING signaling pathway and / or (II) an increase in the level of cGAMP in a serum sample or a tumor sample obtained from the subject; and administering to a subject identified as having a therapeutically effective amount of a STING antagonist or selecting a treatment comprising a pharma- ceutically acceptable salt, solvate, or co-crystal, the STING antagonist is a compound of any one of Formulas I-XXIV or Formulas M1-M6, or a compound shown in Table C1; A method for selecting a treatment for a subject in need thereof, comprising: A composition for a treatment selected by the method of any one of claims 1 to 4, wherein the composition comprises a STING antagonist, or a pharma- ceutically acceptable salt, solvate, or cocrystal thereof.

5. The following steps: (a) Compared to a reference level, (I) (i) a decrease in the level and / or activity of TREX1, and (ii) Increased activity of the cGAS / STING signaling pathway and / or (II) an increase in the level of cGAMP in a serum sample or a tumor sample obtained from the subject; identifying a subject having (b) selecting the identified subjects for treatment with a therapeutically effective amount of a STING antagonist, or a pharma- ceutically acceptable salt, solvate, or cocrystal thereof; the STING antagonist is a compound of any one of Formulas I-XXIV or Formulas M1-M6, or a compound shown in Table C1; A method for selecting a subject for treatment, comprising:

16. A composition for treating a subject selected by the method of claim 15, wherein the composition comprises a STING antagonist, or a pharma- ceutically acceptable salt, solvate, or cocrystal thereof.

6. The following steps: (a) Compared to a reference level, (I) (i) a decrease in the level and / or activity of TREX1, and (ii) Increased activity of the cGAS / STING signaling pathway and / or (II) an increase in the level of cGAMP in a serum sample or a tumor sample obtained from the subject; identifying a subject having (b) selecting the identified subjects for participation in a clinical trial involving administration of a treatment comprising a therapeutically effective amount of a STING antagonist, or a pharma- ceutically acceptable salt, solvate, or cocrystal thereof; the STING antagonist is a compound of any one of Formulas I-XXIV or Formulas M1-M6, or a compound shown in Table C1; Methods for selecting subjects for participation in clinical trials, including 16. A composition for treating a subject selected by the method of claim 15, wherein the composition comprises a STING antagonist, or a pharma- ceutically acceptable salt, solvate, or cocrystal thereof.

7. The following steps: For participation in a clinical trial involving administration of a treatment comprising a therapeutically effective amount of a STING antagonist, or a pharma- ceutically acceptable salt, solvate, or cocrystal thereof, compared to a reference level, (I) (i) a decrease in the level and / or activity of TREX1, and (ii) Increased activity of the cGAS / STING signaling pathway and / or (II) selecting a subject identified as having an elevated level of cGAMP in a serum sample or a tumor sample obtained from the subject, the STING antagonist is a compound of any one of Formulas I-XXIV or Formulas M1-M6, or a compound shown in Table C1; Methods for selecting subjects for participation in clinical trials, including 16. A composition for treating a subject selected by the method of claim 15, wherein the composition comprises a STING antagonist, or a pharma- ceutically acceptable salt, solvate, or cocrystal thereof.

8. The following steps: (a) Compared to a reference level, (I) (i) a decrease in the level and / or activity of TREX1, and (ii) Increased activity of the cGAS / STING signaling pathway and / or (II) an increase in the level of cGAMP in a serum sample or a tumor sample obtained from the subject; determining that the subject has the (b) In step (a), compared with a reference level: (I) (i) a decrease in the expression and / or activity of TREX1, and (ii) Increased activity of the cGAS / STING signaling pathway and / or (II) an increase in the level of cGAMP in a serum sample or a tumor sample obtained from the subject; identifying a subject determined to have an increased likelihood of responding to treatment with a STING antagonist, the STING antagonist is a compound of any one of Formulas I-XXIV or Formulas M1-M6, or a compound shown in Table C1; A method for predicting a subject's responsiveness to a STING antagonist, comprising:

1. A composition for treating a subject as identified in claim 1, wherein the composition comprises a STING antagonist, or a pharma- ceutically acceptable salt, solvate, or cocrystal thereof.

9. The following steps: Compared to the reference level, (I) (i) a decrease in the level and / or activity of TREX1, and (ii) Increased activity of the cGAS / STING signaling pathway and / or (II) an increase in the level of cGAMP in a serum sample or a tumor sample obtained from the subject; identifying a subject determined to have a STING antagonist as having an increased likelihood of responding to treatment with the STING antagonist, the STING antagonist is a compound of any one of Formulas I-XXIV or Formulas M1-M6, or a compound shown in Table C1; A method for predicting a subject's responsiveness to a STING antagonist, comprising:

1. A composition for treating a subject as identified in claim 1, wherein the composition comprises a STING antagonist, or a pharma- ceutically acceptable salt, solvate, or cocrystal thereof.

10. The subject is identified as having cancer cells that have both (i) a decrease in TREX1 level and / or activity, and (ii) an increase in cGAS / STING signaling pathway activity; Optionally, the subject is identified as having an elevated level of cGAMP in a serum sample or a tumor sample obtained from the subject compared to a reference level.

11. The composition of any one of claims 1 to 10, wherein the increased cGAS / STING signaling pathway activity and / or increased levels of cGAMP are the result of a decreased level and / or activity of BRCA1 in the cancer cell.

12. 12. The composition of any one of claims 1 to 11, wherein the increased cGAS / STING signaling pathway activity is the result of a decreased level and / or activity of the BRCA2 gene; or a decreased level and / or activity of SAMHD1 in the cancer cell; or a decreased level and / or activity of DNASE2 in the cancer cell; or a decreased level and / or activity of PARP1 in the cancer cell; or a decreased level and / or activity of RPA1 in the cancer cell; or a decreased level and / or activity of RAD51 in the cancer cell; or an increased level and / or activity of MUS81 in the cancer cell; or an increased level and / or activity of IFI16 in the cancer cell; or an increased level and / or activity of cGAS in the cancer cell; or an increased level and / or activity of DDX41 in the cancer cell; or an increased level and / or activity of EXO1 in the cancer cell; an increased level and / or activity of DNA2 in the cancer cell; or an increased level and / or activity of RBBP8 (CtIP) in the cancer cell; or an increased level and / or activity of MRE11 in the cancer cell.

13. The composition of any one of claims 1 to 11, wherein the increased cGAS / STING signaling pathway activity and / or elevated levels of cGAMP are the result of decreased levels and / or activity of BLM in the cancer cell.

14. The composition of any one of claims 1 to 11, wherein the increased cGAS / STING signaling pathway activity is the result of a gain-of-function mutation in STING.

15. The composition of claim 3 or 4, wherein the method further comprises administering the selected treatment to a subject.

16. The composition of claim 8 or 9, wherein the method further comprises administering a therapeutically effective amount of a STING antagonist to a subject identified as having an increased likelihood of responding to treatment with a STING antagonist.

17. The composition of any one of claims 1 to 16, wherein the subject has been diagnosed or identified as having cancer, such as a cancer selected from the group consisting of renal clear cell carcinoma, papillary renal cell carcinoma, chromophobe renal cell carcinoma, uveal melanoma, tongue squamous cell carcinoma, breast cancer, osteosarcoma, and skin cancer.

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