Pharmaceutical combination of a FAK inhibitor and a microtubule inhibitor, and uses thereof

Abstract

Compositions of FAK inhibitors, microtubule inhibitors and immune checkpoint inhibitors, kits comprising the compositions, and their use in the preparation of medicaments for treating tumors are provided.

Description

[Technical Field]

[0001] This application claims priority to Chinese Patent Application Publication No. 202211018821.9, filed on August 24, 2022, Chinese Patent Application Publication No. 202211165722.3, filed on September 23, 2022, and Chinese Patent Application Publication No. 202310940775.6, filed on July 28, 2023. The disclosures of the above-referenced Chinese patent applications are incorporated herein by reference in their entirety.

[0002] The present disclosure is in the field of medicinal chemistry. Specifically, the present disclosure relates to the treatment of tumors using focal adhesion kinase (FAK) inhibitors in combination with other drugs. [Background technology]

[0003] Tumors are the second largest and most lethal threat to human health. Immunogenic cell death (ICD) is based on the superposition effect of programmed cell death. Intracellular pressure signals can be activated when cancer cells are exposed to chemotherapy or targeted drugs. These pressure signals include endoplasmic reticulum pressure (ER stress) and reactive oxygen species pressure (oxidative stress). Under the influence of pressure signals, cells first attempt to repair the stress. If the damage caused by the pressure exceeds the cell's repair capacity, the cell initiates the programmed death process. This process is often accompanied by the release of a class of damage-associated molecular patterns (DAMPs), including calreticulin, annexin A1, and HMGB1. This type of DAMP is specifically recognized by pattern recognition receptors on antigen-presenting cells (APCs) in the body, and the DAMP induces the maturation, differentiation, and activation of APCs, which then gradually present them to immune cells, such as effector T cells, thus generating antigen memory in the immune cells. If tumor cells from the same source are found again, the immune cells will specifically recognize and kill the tumor cells. The new tumor-specific immune response initiated by ICD increases sensitivity to immune checkpoint inhibitors (ICIs), thereby enhancing the effectiveness of immune checkpoint inhibitors and generating anti-tumor responses to maintain immune memory.

[0004] FAK, also known as protein tyrosine kinase 2 (PTK2), is a non-receptor tyrosine kinase and a key component of focal adhesion complexes. FAK mediates integrin and growth factor signals and plays an important role in mediating tumor cell invasion, proliferation, and survival.

[0005] Microtubules are dynamic, filamentous cytoskeletal proteins and the main molecules of centrioles. Regular dynamic changes of microtubule fibers are an important guarantee of cell mitosis. Microtubule inhibitors bind to tubulin to promote or inhibit microtubule assembly, disrupt the normal structure and function of the microtubule-based mitotic spindle, inhibit cell mitosis, inhibit cell proliferation, and exert clear antitumor effects. Antitumor drugs targeting microtubules are becoming an important aspect of current antitumor drug research. Many microtubule inhibitors are currently on the market, including taxanes and eribulin. Taxanes include paclitaxel extracted from natural tree bark, synthetic docetaxel, and more recently, albumin paclitaxel. Taxanes are M-phase cycle-specific drugs that can promote the polymerization of tubulin into stable microtubules and inhibit its depolymerization, thereby significantly reducing the number of tubules and disrupting the microtubule network structure. Eribulin is a synthetic analog of halichondrin B that inhibits microtubule depolymerization, thereby causing G2 / M block in the cell cycle and disruption of the mitotic spindle, ultimately leading to cell apoptosis. Both taxanes and eribulin are commonly used chemotherapy drugs in hospitals. However, both drugs develop some degree of drug resistance after a period of administration. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] International Publication No. 2010058032 Summary of the Invention [Problem to be solved by the invention]

[0007] Therefore, there remains a need to find ways to improve the efficacy of single agents in chemotherapy and also to further overcome the problem of drug resistance. [Means for solving the problem]

[0008] One aspect of the present disclosure provides use of a FAK inhibitor, a microtubule inhibitor, and an immune checkpoint inhibitor in the manufacture of a medicament for treating a tumor in a subject.

[0009] Yet another aspect of the present disclosure provides a pharmaceutical combination of a FAK inhibitor, a microtubule inhibitor, and an immune checkpoint inhibitor for use in treating a tumor in a subject.

[0010] Yet another aspect of the present disclosure provides a method for treating a tumor, the method comprising administering therapeutically effective amounts of a FAK inhibitor, a microtubule inhibitor, and an immune checkpoint inhibitor to a subject in need thereof.

[0011] Yet another aspect of the present disclosure provides a kit or a pharmaceutically acceptable composition comprising (a) a FAK inhibitor, (b) a microtubule inhibitor, and (c) an immune checkpoint inhibitor.

[0012] Yet another aspect of the present disclosure provides the use of a FAK inhibitor and a microtubule inhibitor in the manufacture of a medicament for treating a tumor, wherein the FAK inhibitor is used to enhance immunogenic cell death induced by the microtubule inhibitor.

[0013] Yet another aspect of the present disclosure provides a FAK inhibitor for use in enhancing immunogenic cell death induced by microtubule inhibitors in the treatment of tumors.

[0014] Yet another aspect of the present disclosure provides a method for treating a tumor, comprising administering therapeutically effective amounts of a FAK inhibitor and a microtubule inhibitor to a subject in need thereof, wherein the FAK inhibitor is used to enhance immunogenic cell death induced by the microtubule inhibitor.

[0015] Yet another aspect of the present disclosure provides the use of a FAK inhibitor, a microtubule inhibitor and an immune checkpoint inhibitor in the manufacture of a medicament for the combined treatment of a tumor.

[0016] Yet another aspect of the present disclosure provides the use of a FAK inhibitor in the manufacture of a combination medicament with a microtubule inhibitor and an immune checkpoint inhibitor for treating a tumor.

[0017] Yet another aspect of the present disclosure provides the use of a microtubule inhibitor in the manufacture of a combination medicament with a FAK inhibitor and an immune checkpoint inhibitor for treating a tumor.

[0018] Yet another aspect of the present disclosure provides the use of an immune checkpoint inhibitor in the manufacture of a combination medicament with a FAK inhibitor and a microtubule inhibitor for treating a tumor.

[0019] Yet another aspect of the present disclosure provides the use of a FAK inhibitor in the manufacture of a medicament for the combined treatment of a tumor with a microtubule inhibitor and an immune checkpoint inhibitor.

[0020] Yet another aspect of the present disclosure provides the use of a microtubule inhibitor in the manufacture of a medicament for the combined treatment of a tumor with a FAK inhibitor and an immune checkpoint inhibitor.

[0021] Yet another aspect of the present disclosure provides the use of an immune checkpoint inhibitor in the manufacture of a medicament for the combined treatment of a tumor with a FAK inhibitor and a microtubule inhibitor.

[0022] Yet another aspect of the present disclosure provides a kit comprising a FAK inhibitor and instructions for use, wherein the instructions indicate that the FAK inhibitor can be used in combination with a microtubule inhibitor and an immune checkpoint inhibitor to treat a tumor.

[0023] Yet another aspect of the present disclosure provides a kit comprising a microtubule inhibitor and instructions for use, wherein the instructions indicate that the microtubule inhibitor can be used in combination with a FAK inhibitor and an immune checkpoint inhibitor to treat a tumor.

[0024] Yet another aspect of the present disclosure provides a kit comprising an immune checkpoint inhibitor and instructions for use, wherein the instructions indicate that the immune checkpoint inhibitor can be used in combination with a FAK inhibitor and a microtubule inhibitor to treat a tumor.

[0025] Yet another aspect of the present disclosure provides a method for treating a tumor, comprising administering therapeutically effective amounts of a FAK inhibitor and a microtubule inhibitor to a subject in need thereof.

[0026] Yet another aspect of the present disclosure provides a pharmaceutical combination of a FAK inhibitor and a microtubule inhibitor for use in treating a tumor in a subject in need thereof.

[0027] Yet another aspect of the present disclosure provides the use of a FAK inhibitor and a microtubule inhibitor in the manufacture of a combined medicament for treating a tumor.

[0028] Yet another aspect of the present disclosure provides the use of a FAK inhibitor in the manufacture of a combination medicament with a microtubule inhibitor for treating a tumor.

[0029] Yet another aspect of the present disclosure provides the use of a microtubule inhibitor in the manufacture of a combination medicament with a FAK inhibitor for treating a tumor.

[0030] Yet another aspect of the present disclosure provides the use of a FAK inhibitor and a microtubule inhibitor in the manufacture of a medicament for the combined treatment of a tumor.

[0031] Yet another aspect of the present disclosure provides the use of a FAK inhibitor in the manufacture of a medicament for the combined treatment of a tumor with a microtubule inhibitor.

[0032] Yet another aspect of the present disclosure provides the use of a microtubule inhibitor in the manufacture of a medicament for the combined treatment of a tumor with a FAK inhibitor.

[0033] Yet another aspect of the present disclosure provides a kit comprising a FAK inhibitor and instructions for use, wherein the instructions indicate that the FAK inhibitor can be used in combination with a microtubule inhibitor to treat tumors.

[0034] Yet another aspect of the present disclosure provides a kit comprising a microtubule inhibitor and instructions for use, the instructions indicating that the microtubule inhibitor can be used in combination with a FAK inhibitor to treat tumors.

[0035] Optionally, the FAK inhibitor is IN10018, defactinib, GSK2256098, PF-00562271, VS-4718, APG-2449, AMP945, AMP886 or a pharmaceutically acceptable salt thereof, or IN10018, defactinib, AMP945 or a pharmaceutically acceptable salt thereof, further or IN10018 or a pharmaceutically acceptable salt thereof, or IN10018 tartrate, wherein the structure of IN10018 is:

[0036] [ka]

[0037] is.

[0038] Defactinib is also known as difatini with CAS number 1345713-71-4, GSK2256098 with CAS number 1224887-10-8, PF-00562271 with CAS number 717907-75-0, VS-4718 with CAS number 1061353-68-1, APG-2449 is being developed by Ascent Pharmaceuticals, and AMP945 with CAS number 1393653-34-3.

[0039] Optionally, the microtubule inhibitor is a taxane, eribulin, Ixempra, or a vinca alkaloid.

[0040] Optionally, the microtubule inhibitor is a taxane.

[0041] Optionally, the taxane is docetaxel, paclitaxel, cabazitaxel or cephalomannine, or is docetaxel or paclitaxel.

[0042] Optionally, the microtubule inhibitor is docetaxel.

[0043] Optionally, the microtubule inhibitor is paclitaxel.

[0044] Paclitaxel or docetaxel includes formulations thereof, such as paclitaxel liposome, albumin paclitaxel, and the like.

[0045] Optionally, the microtubule inhibitor is eribulin, which is also known as Erebulin / Halaven and has a CAS number of 253128-41-5.

[0046] Optionally, the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, a PD-1 / PD-L1 small molecule inhibitor, or a TIGIT inhibitor.

[0047] Optionally, the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, and alternatively, the anti-PD-1 / PD-L1 antibody is pembrolizumab, tislelizumab, nivolumab, toripalimab, atezolizumab, durvalumab, avelumab, camrelizumab, sintilimab, cemiplimab, embafolimab, BMS-936559, JS003, SHR-1316, GS-4224, AN-4005, or MX-10181.

[0048] Optionally, the immune checkpoint inhibitor is a PD-1 / PD-L1 small molecule inhibitor, and alternatively, the PD-1 / PD-L1 small molecule inhibitor is INCB-086550, lazertinib, IMMH-010, CA-170, ABSK043, or RRx-001.

[0049] Optionally, the immune checkpoint inhibitor is a TIGIT inhibitor; or alternatively, the TIGIT inhibitor is osipellimab (BGB-A1217), vibostolimab, domvanalimab (AB154), tiragolumab, berlestog, etigilimab, ONO-4686, JS-006, AZD-2936, HLX-301, SEA-TGT, M-6223, IBI-939, COM-902, AB-308, AGEN-1777, AK-127, BAT-6021, BAT-6005, ASP-8374, PM-1022, BMS-986207, HB0036, or IBI-321.

[0050] Optionally, the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the microtubule inhibitor is docetaxel, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor.

[0051] Optionally, the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the microtubule inhibitor is docetaxel, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody.

[0052] Optionally, the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the microtubule inhibitor is paclitaxel, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor.

[0053] Optionally, the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the microtubule inhibitor is paclitaxel, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody.

[0054] Optionally, the FAK inhibitor, microtubule inhibitor and immune checkpoint inhibitor are administered to the subject simultaneously or sequentially.

[0055] Optionally, the tumor is selected from the group consisting of bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer, liver cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma, myeloma, rhabdomyosarcoma, inflammatory myofibroblastoma, neuroblastoma, pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), gastric cancer, testicular cancer, thyroid cancer, uterine cancer, mesothelioma, cholangiocarcinoma, leiomyosarcoma, liposarcoma, and esophageal cancer. metastases caused by pharyngeal carcinoma, neuroendocrine carcinoma, ovarian cancer, salivary gland cancer, spindle cell carcinoma, anaplastic large cell lymphoma, anaplastic thyroid carcinoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, glioma or hematological malignancies such as acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL) or chronic myeloid leukemia (CML).

[0056] Optionally, the tumor is breast cancer, ovarian cancer, colon cancer (including colorectal cancer), lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma, or pancreatic cancer.

[0057] Optionally, the tumor is breast cancer, ovarian cancer, or colon cancer (including colorectal cancer).

[0058] In order to more clearly describe the exemplary technical solutions of the present disclosure, exemplary drawings are briefly introduced below. Needless to say, the drawings in the following description only relate to some examples of the present disclosure, and do not limit the present disclosure. [Brief explanation of the drawings]

[0059] [Figure 1] FIG. 1 shows staining using Annexin V kit after 48 hours of FAK silencing in combination with 0.3 μM or 1 μM docetaxel. [Figure 2] FIG. 1 shows that 48 h of FAK silencing in combination with 1 μM docetaxel enhanced calreticulin release and exposure. [Figure 3]FIG. 1 shows staining using Annexin V kit after 48 hours of FAK silencing in combination with 0.15 μM eribulin. [Figure 4] FIG. 1 shows that 48 h of FAK silencing in combination with 0.15 μM eribulin enhanced calreticulin release and exposure. [Figure 5] FIG. 1 shows IC50 values ​​of docetaxel in combination with IN10018 in colon cancer cells CT26. [Figure 6] FIG. 1 shows white light micrographs of colon cancer CT26 cells after 48 hours of incubation with drugs. [Figure 7a] FIG. 1 shows the percentage of CRT-positive cells after 48 hours of incubation of colon cancer CT26 cells with drugs. [Figure 7b] Figure 1 shows the percentage of Annexin V-positive cells after 48 hours of incubation of colon cancer CT26 cells with drugs. [Figure 8a] FIG. 1 shows the percentage of calreticulin (CRT) positive cells after 48 hours of incubation of mouse breast cancer 4T1 cells with drugs. [Figure 8b] FIG. 1 shows the percentage of Annexin-V positive cells after 48 hours of incubation of mouse breast cancer 4T1 cells with drugs. [Figure 8c] FIG. 1 shows the percentage of GRP94-positive cells after 48 hours of incubation of mouse breast cancer 4T1 cells with drugs. [Figure 9a] FIG. 1 shows the percentage of calreticulin (CRT) positive cells after incubation of mouse ovarian epithelial carcinoma ID8 cells with drugs for 48 hours. [Figure 9b] Figure 1 shows the percentage of Annexin-V positive cells after incubation of mouse ovarian epithelial carcinoma ID8 cells with drugs for 48 hours. [Figure 10a]FIG. 1 shows the percentage of calreticulin (CRT) positive cells after incubating human ovarian epithelial carcinoma TOV-21G cells with drugs for 48 hours. [Figure 10b] FIG. 1 shows the percentage of Annexin-V positive cells after 48 hours of incubation of human ovarian epithelial carcinoma TOV-21G cells with drugs. [Figure 11a] FIG. 1 shows the percentage of calreticulin (CRT) positive cells after incubation of mouse colon carcinoma CT26 cells with docetaxel and other drugs for 48 hours. [Figure 11b] FIG. 1 shows the percentage of Annexin-V positive cells after incubation of mouse colon carcinoma CT26 cells with docetaxel and other drugs for 48 hours. [Figure 12a] FIG. 1 shows the percentage of calreticulin (CRT) positive cells after incubation of mouse colon carcinoma CT26 cells with eribulin and other drugs for 48 hours. [Figure 12b] FIG. 1 shows the percentage of Annexin-V positive cells after incubation of mouse colon carcinoma CT26 cells with eribulin and other drugs for 48 hours. [Figure 13a] FIG. 1 shows the percentage of calreticulin (CRT) positive cells after incubation of mouse colon carcinoma CT26 cells with paclitaxel and other drugs for 48 hours. [Figure 13b] FIG. 1 shows the percentage of Annexin-V positive cells after 48 hours of incubation of mouse colon carcinoma CT26 cells with paclitaxel and other drugs. [Figure 14a] FIG. 1 shows the percentage of calreticulin (CRT) positive cells after incubation of mouse breast cancer 4T1 cells with docetaxel and other drugs for 48 hours. [Figure 14b] FIG. 1 shows the percentage of Annexin-V positive cells after 48 hours of incubation of mouse breast cancer 4T1 cells with docetaxel and other drugs. [Figure 15a] FIG. 1 shows the percentage of calreticulin (CRT) positive cells after incubation of mouse breast cancer 4T1 cells with eribulin and other drugs for 48 hours. [Figure 15b] FIG. 1 shows the percentage of Annexin-V positive cells after incubating mouse breast cancer 4T1 cells with eribulin and other drugs for 48 hours. [Figure 16] FIG. 1 shows changes in tumor volume after administration of different test substances in a subcutaneous BALB / c mouse allograft tumor model of breast cancer 4T1 cells. [Figure 17] FIG. 1 shows changes in mouse body weight after administration of different test substances in a subcutaneous BALB / c mouse allograft tumor model of breast cancer 4T1 cells. [Figure 18a] FIG. 1 shows the percentage of calreticulin (CRT) positive cells after incubation of mouse breast cancer 4T1 cells with docetaxel and other drugs for 48 hours. [Figure 18b] FIG. 1 shows the percentage of Annexin-V positive cells after 48 hours of incubation of mouse breast cancer 4T1 cells with docetaxel and other drugs. [Figure 19a] FIG. 1 shows the percentage of calreticulin (CRT) positive cells after incubation of mouse breast cancer 4T1 cells with eribulin and other drugs for 48 hours. [Figure 19b] FIG. 1 shows the percentage of Annexin-V positive cells after incubating mouse breast cancer 4T1 cells with eribulin and other drugs for 48 hours. DETAILED DESCRIPTION OF THE INVENTION

[0060] In order to make the objectives, technical solutions and advantages of the examples of the present disclosure more apparent, the technical solutions of the examples of the present disclosure are clearly and completely described in the accompanying drawings. Needless to say, the described examples are only a part of the examples of the present disclosure, but are not all of the examples. Based on the described examples of the present disclosure, all other examples obtained by those skilled in the art without creative work belong to the scope of protection of the present disclosure.

[0061] The present disclosure may be embodied in other specific forms without departing from the basic attributes of the present disclosure. It should be understood that any and all embodiments of the present disclosure may be combined with technical features of any other embodiment or embodiments to obtain additional embodiments without inconsistency. The present disclosure includes further embodiments resulting from such combinations.

[0062] All publications and patents mentioned in this disclosure are hereby incorporated by reference in their entirety. In the event that the usage in, or terminology used in, any publication or patent incorporated by reference conflicts with the usage in, or terminology used in, this disclosure, the usage and terminology of this disclosure shall control.

[0063] The section headings used in this disclosure are for organizational purposes only and are not to be construed as limitations on the subject matter.

[0064] Unless otherwise defined, all technical and scientific terms used herein have their ordinary meaning within the field to which the claimed subject matter belongs. In the event that there are a plurality of definitions for a term, those in this disclosure shall prevail.

[0065] Except in the working examples or where otherwise indicated, all numbers of quantitative nature, such as dosage amounts set forth in the description and claims, are to be understood in all instances to be modified by the term "about." It is also to be understood that any numerical range recited in this application is intended to include all subranges within the range, and any combination of the endpoints of the ranges or subranges.

[0066] As used in this disclosure, "including," "containing," "comprising," and the like mean that the elements appearing before the term cover the elements listed after the term and their equivalents, and do not exclude elements not listed. The terms "including," "containing," and "comprising" as used herein can be open, semi-open, and closed. In other words, the terms also include "consisting essentially of" or "consisting of."

[0067] definition As used in this application, the following terms and symbols have the following meanings, unless the context indicates otherwise: As used herein, the term "FAK inhibitor" refers to an effective inhibitor of FAK, which may be suitable for mammals, particularly humans. In some embodiments, the FAK inhibitor is IN10018, defactinib, GSK2256098, PF-00562271, VS-4718, APG-2449, AMP945, AMP886, or a pharmaceutically acceptable salt thereof, and the structure of IN10018 is:

[0068] [ka]

[0069] defactinib, also known as difatin, has a CAS number of 1345713-71-4; GSK2256098 has a CAS number of 1224887-10-8; PF-00562271 has a CAS number of 717907-75-0; VS-4718 has a CAS number of 1061353-68-1; APG-2449 is being developed by Yasheng Medicine Co., Ltd.; and AMP945 has a CAS number of 1393653-34-3. In some embodiments, the FAK inhibitor is alternatively IN10018, defactinib, or a pharmaceutically acceptable salt thereof, and in some alternative embodiments, the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, particularly IN10018 tartrate.

[0070] As used herein, the term "microtubule inhibitor" refers to an effective inhibitor of microtubules / tubulin that may be suitable for mammals, particularly humans. Microtubules are part of the cytoskeleton and are distributed throughout the cytoplasm. Tubulin is one of several members of a small family of globulins. The tubulin superfamily includes five distinct families, α, β, γ, δ, and ε tubulin, with a sixth family found only in embryonic protozoa of plants and animals. The most common members of the tubulin family are α-tubulin and β-tubulin, which are proteins that constitute microtubules. Microtubule inhibitors bind to tubulin and promote or inhibit microtubule assembly, interfere with the normal structure and function of the mitotic spindle, which is composed of microtubules, have the effect of interfering with cell mitosis, inhibit cell proliferation, and exert clear antitumor effects. Microtubule inhibitors are a large class of chemotherapeutic drugs, including taxanes, eribulin, ixabepilone, and vinca alkaloids.

[0071] The term "taxane" as used herein refers to a large class of chemotherapy drugs that includes paclitaxel, which is extracted from natural tree bark, and synthetic docetaxel. For the avoidance of doubt, references to paclitaxel or docetaxel in the claims of this disclosure include formulations thereof, such as paclitaxel liposomes, albumin paclitaxel, etc.

[0072] Eribulin is also known as Elebulin / Halaven and its CAS number is 253128-41-5.

[0073] Ixabepilone is also known as ixabepilone, azaepothilone B or BMS-247550, and its CAS number is 219989-84-1.

[0074] As used herein, the term "immune checkpoint inhibitor" refers to a pharmaceutical agent that can improve immune system activity by modulating immune checkpoint pathways (e.g., PD-1, TIGIT, CTLA-4, LAG-3, TIM-3, etc.). In some embodiments, the immune checkpoint inhibitor is a PD-1 / PD-L1 (programmed cell death protein 1) pathway antagonist (also referred to as a "PD-1 inhibitor") or a TIGIT inhibitor. PD-1 inhibitors are also referred to as PD-1 / PD-L1 inhibitors in the present disclosure. For example, in the therapeutic methods, medicaments, and uses disclosed herein, the PD-1 / PD-L1 inhibitor is a PD-1 / PD-L1 antibody, including, but not limited to, pembrolizumab (pabolizumab) (KERIDA / Keytruda / K medicament), tislelizumab (Baizean), nivolumab, toripalimab (Tuoyi), durvalumab (Imfinzi), avelumab (Bavencio), atezolizumab (MPDL 3280A / Tecentriq / T medicament), BMS-936559 (a fully humanized IgG4 monoclonal antibody against PD-L1), GS-4224, AN-4005, or MX-10181. In some alternative embodiments, the PD-1 inhibitor is toripalimab. In some embodiments, the PD-1 inhibitor is used to treat a human subject. In some embodiments, the PD-1 is human PD-1.

[0075] PD-1 / PD-L1 inhibitors also include PD-1 / PD-L1 small molecule inhibitors. In some embodiments, the PD-1 / PD-L1 small molecule inhibitor is INCB-086550, lazertinib, IMMH-010, CA-170, ABSK043, or RRx-001.

[0076] TIGIT (also known as WUCAM, Vstm3, and VSIG9) is a receptor of the Ig superfamily and a novel immune checkpoint in addition to PD-1 / PD-L1. For example, in the therapeutic methods, medicaments, and uses disclosed herein, the PD-1 / PD-L1 inhibitor is a TIGIT inhibitor, including, but not limited to, osipellimab (BGB-A1217), vibostolimab, domvanalimab (AB154), tiragolumab, berlestog, etigilimab, ONO-4686, JS-006, AZD-2936, HLX-301, SEA-TGT, M-6223, IBI-939, COM-902, AB-308, AGEN-1777, AK-127, BAT-6021, BAT-6005, ASP-8374, PM-1022, BMS-986207, HB0036, or IBI-321. In some embodiments, the TIGIT inhibitor is used to treat a human subject. For the avoidance of doubt, all antibodies in this disclosure include biantibodies.

[0077] As used herein, "pharmaceutical combination" or "pharmaceutical combination" can refer to the case of a fixed combination in the form of a dosage unit (e.g., all active pharmaceutical ingredients present in one dosage form), or to the case of products that are administered in combination in a completed kit, as well as to the case of a combination of pharmaceuticals and instructions for use indicating that the pharmaceutical can be used in combination with one or more other pharmaceuticals.

[0078] As used herein, "combination treatment" or "combined medication" means that a medication is used in combination with one or more other medications to treat a disease, and includes both a combination of one medication and one or more other medications, and a combination of one medication and instructions indicating that the medication may be used in combination with one or more other medications.

[0079] In this application, "simultaneous or sequential administration" refers to simultaneous administration of two or more pharmaceutical agents or sequential administration of two or more pharmaceutical agents at a time interval within an administration cycle (e.g., within 4 weeks, 3 weeks, 2 weeks, 1 week, or 24 hours). The mode of administration (e.g., oral administration, intravenous administration, intramuscular administration, or subcutaneous administration) may be the same or different, and the number / cycle of administration of two or more pharmaceutical agents may be the same or different. When the therapeutic method, product, or use of the present disclosure involves two pharmaceutical agents, the two pharmaceutical agents may be administered simultaneously or separately at a certain interval. When the therapeutic method, product, or use of the present disclosure involves three pharmaceutical agents, the three pharmaceutical agents may be administered at the same time, or two pharmaceutical agents may be administered at one time and one pharmaceutical agent at another time, or each of the three pharmaceutical agents may be administered at different time points.

[0080] In some embodiments, the PD-1 / PD-L1 inhibitor is administered intravenously (e.g., as an intravenous injection), subcutaneously, or orally. Alternatively, the PD-1 / PD-L1 inhibitor is administered by intravenous injection.

[0081] In some embodiments, the TIGIT inhibitor is administered intravenously (e.g., as an intravenous injection), subcutaneously, or orally. Alternatively, the TIGIT inhibitor is administered by intravenous injection.

[0082] The ability of immune checkpoint inhibitors to treat cancer depends on the presence of tumor antigen-specific T cells in tumor tissue. This requires tumor tissue to express antigens that distinguish it from its non-transformed counterparts, for example, through new protein products called neoantigens. The neoantigen burden of a tumor is closely related to immunogenicity and susceptibility (e.g., susceptibility to checkpoint inhibitor treatment), meaning that poorly immunogenic tumors should be highly resistant to these drugs. Therapeutic agents that release tumor antigens that can be ingested by APCs, such as those that induce immunogenic cell death (ICD), can promote effective anti-tumor immunity, especially when further combined with checkpoint inhibitors.

[0083] As used herein, the term "treatment" refers to the administration of one or more pharmaceutical agents to a subject suffering from a disease or having symptoms of a disease to cure, alleviate, relieve, alter, treat, improve, ameliorate, or affect the disease or symptoms of the disease. In some embodiments, the disease is a tumor or cancer.

[0084] The term "tumor" as used herein refers to an abnormal pathological change formed by the abnormal proliferation of clonal cells caused by the loss of normal regulation of cell growth in local tissues at the genetic level under the action of various tumorigenic factors. Tumors include bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer, liver cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma, myeloma, rhabdomyosarcoma, inflammatory myofibroblastoma, neuroblastoma, pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), gastric cancer, testicular cancer, thyroid cancer, uterine cancer, mesothelioma, cholangiocarcinoma, leiomyosarcoma, liposarcoma, nasopharyngeal cancer, neuroendocrine cancer, and the like. Cancer, including, but not limited to, ovarian cancer, salivary gland cancer, metastases caused by spindle cell carcinoma, anaplastic large cell lymphoma, anaplastic thyroid carcinoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, glioma, or hematological malignancies such as acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), or chronic myelogenous leukemia (CML). In some embodiments, the tumor is alternatively breast cancer, ovarian cancer, colon cancer (including colorectal cancer), lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma, or pancreatic cancer; in some embodiments, the tumor is breast cancer, ovarian cancer, or colon cancer (including colorectal cancer).

[0085] As used herein, the term "subject" or "patient" refers to mammals and non-mammals. Mammals refer to any member of the mammalian genus, including, but not limited to, humans; non-human primates, such as chimpanzees and other ape and monkey species; agricultural animals, such as cows, horses, sheep, goats, and pigs; livestock, such as rabbits, dogs, and cats; and laboratory animals, including rodents, such as rats, mice, and guinea pigs. Examples of non-mammals include, but are not limited to, birds, and the like. The term "subject" is not limited to a particular age or sex. In some embodiments, the subject is a human.

[0086] As used herein, the term "pharmaceutically acceptable" means non-toxic, biologically tolerable and suitable for administration to a subject.

[0087] As used herein, the term "pharmaceutically acceptable salt" includes acid addition salts formed with inorganic acids, such as hydrochlorides, hydrobromides, carbonates, bicarbonates, phosphates, sulfates, sulfites, nitrates, and the like; and acid addition salts with organic acids, such as formates, acetates, malates, maleates, fumarates, tartrates, succinates, citrates, lactates, methanesulfonates, p-toluenesulfonates, 2-hydroxyethylsulfonates, benzoates, salicylates, stearates, and salts of the formula HOOC-(CH) n This refers to non-toxic and biologically tolerable acid addition salts suitable for administration to a subject, including, but not limited to, salts formed with alkanedicarboxylic acids of —COOH (where n is 0 to 4).

[0088] Additionally, pharmaceutically acceptable acid addition salts can be obtained by dissolving the free base in a suitable solvent and treating the solution with an acid, following conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art can determine, without undue experimentation, various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable acid addition salts.

[0089] As used herein, the term "pharmaceutically acceptable composition" means that the composition must be chemically and / or toxicologically compatible with other ingredients included in the preparation and / or compatible with the subject being treated. As used herein, the term "therapeutically effective amount" refers to an amount generally sufficient to produce a beneficial therapeutic effect in a subject. The therapeutically effective amount of the present disclosure can be determined by conventional methods (e.g., modeling, dose escalation studies, or clinical trials) in combination with conventional influencing factors (e.g., mode of administration, pharmacokinetics of the compound, severity and course of the disease, medical history of the subject, health status of the subject, degree of response of the subject to the medication, etc.).

[0090] As used herein, the term "inhibition" refers to a decrease in the baseline activity of a biological activity or process.

[0091] As used herein, the term "kit" refers to a box containing chemical reagents for detecting chemical components, drug residues, virus types, etc. The kits of the present disclosure may include (i) one, two, or three of a FAK inhibitor, a microtubule inhibitor, and an immune checkpoint inhibitor; and (ii) instructions for use indicating that the FAK inhibitor, the microtubule inhibitor, and the immune checkpoint inhibitor may be used to treat a tumor in a subject. In one embodiment, the kit includes (i) a FAK inhibitor; and (ii) instructions for use indicating that the FAK inhibitor, the microtubule inhibitor, and the immune checkpoint inhibitor may be used to treat a tumor in a subject. In one embodiment, the kit includes (i) a microtubule inhibitor; and (ii) instructions for use indicating that the FAK inhibitor, the microtubule inhibitor, and the immune checkpoint inhibitor may be used to treat a tumor in a subject. In one embodiment, the kit includes (i) an immune checkpoint inhibitor; and (ii) instructions for use indicating that the FAK inhibitor, the microtubule inhibitor, and the immune checkpoint inhibitor may be used to treat a tumor in a subject. In one embodiment, the kit comprises (i) a FAK inhibitor, a microtubule inhibitor, and an immune checkpoint inhibitor; and (ii) instructions for use indicating that the FAK inhibitor, the microtubule inhibitor, and the immune checkpoint inhibitor can be used to treat a tumor in a subject. In one embodiment, the kit comprises (i) a FAK inhibitor; and (ii) instructions for use indicating that the FAK inhibitor and the microtubule inhibitor can be used to treat a tumor in a subject. In one embodiment, the kit comprises (i) a microtubule inhibitor; and (ii) instructions for use indicating that the microtubule inhibitor and the FAK inhibitor can be used to treat a tumor in a subject.

[0092] The compounds of the kit may be contained in separate containers. Optionally, two or more compounds are contained in the same container. For example, the kit may include a first container, a second container, a third container, and a package insert, where the first container contains at least one dose of a medicament comprising a FAK inhibitor, the second container contains at least one dose of a microtubule inhibitor, and the third container contains at least one dose of a medicament comprising an immune checkpoint inhibitor, and the package insert includes instructions for treating a tumor in a subject with the medicament. The first container, the second container, and the third container may contain the same or different shapes (e.g., vials, syringes, and bottles) and / or materials (e.g., plastic or glass). The kit may also include other materials that may aid in administering the medicament, such as diluents, filters, IV bags and lines, needles, and syringes.

[0093] The exact amount of FAK inhibitor, microtubule inhibitor, and immune checkpoint inhibitor administered to a subject will depend on various factors, such as the specific drug or compound, pharmaceutical agent, route of administration, type of disease, symptoms, and identity of the subject or host being treated, but can nevertheless be routinely determined by one of ordinary skill in the art. For example, determining an effective amount also depends on the degree, severity, and type of cell proliferation. Those of ordinary skill in the art will be able to determine appropriate dosages based on these and other factors.

[0094] The FAK inhibitor, microtubule inhibitor and immune checkpoint inhibitor may be administered in any suitable manner, for example orally, intravenously, intramuscularly or subcutaneously.

[0095] For example, when administered orally, the medicament may be orally administered with a pharmaceutically acceptable carrier, such as an inert diluent or an assimilable edible carrier. These may be encapsulated in hard or soft-shell gelatin capsules, compressed into tablets, or mixed directly with the patient's food. For example, the medicament may be combined with one or more excipients and used in the form of an ingestible tablet, oral tablet, lozenge, capsule, elixir, suspension, syrup, or wafer. Tablets, lozenges, pills, capsules, etc. may further contain a binder such as tragacanth gum, gum arabic, corn starch, or gelatin; an excipient such as dicalcium phosphate; a disintegrant such as corn starch, potato starch, alginic acid, etc.; a lubricant such as magnesium stearate; or a sweetener such as sucrose, fructose, lactose, or aspartame; or a flavoring agent.

[0096] For example, when administered intravenously or intraperitoneally by injection or infusion, pharmaceutical solutions can be prepared in water, optionally mixed with a nontoxic surfactant.

[0097] Exemplary pharmaceutical dosage forms for infusion or injection include sterile aqueous solutions, dispersions, or sterile powders containing the active ingredient suitable for temporarily preparing sterile infusion or injection solutions or dispersions. In all cases, the ultimate dosage form should be sterile, fluid, and stable under the conditions of manufacture and storage.

[0098] Sterile injectable solutions can be prepared by mixing the required amount of the drug with various other ingredients mentioned above in a suitable solvent, and then filtering and sterilizing the mixture. For sterile powders used to prepare sterile injectable solutions, alternative preparation methods can be vacuum drying and freeze-drying techniques, which can produce powders of the active ingredient and any other ingredients required after the aforementioned sterile filtration.

[0099] The amount of FAK inhibitor, microtubule inhibitor, and immune checkpoint inhibitor required for treatment may vary depending not only on the specific reagent selected, but also on the route of administration, the nature of the disease being treated, and the age and condition of the patient, and can be ultimately determined by the attending physician. However, in general, the dosage can be in the range of about 0.1 to about 50 mg / kg body weight per day.

[0100] The FAK inhibitor is administered in a dosage range of 5 mg / day to 300 mg / day in adults. In certain embodiments, IN10018 or a pharmaceutically acceptable salt thereof is administered in a dose of 5 mg / day to 100 mg / day in adults. In certain embodiments, IN10018 or a pharmaceutically acceptable salt thereof is administered in a dose of 25 mg / day to 100 mg / day in adults, the dose being calculated as the free base.

[0101] Microtubule inhibitors are administered at a dose of 20 to 60 mg / m per week for adults. 2 In certain embodiments, docetaxel is administered at a dose of 20-25 mg / m per week for adults. 2 Paclitaxel or its preparations are administered at a dose of 45 to 60 mg / m per week for adults, calculated as paclitaxel. 2 Eribulin was administered at a dose of 1.4 mg / m over 2 to 5 minutes on days 1 and 8 of a 21-day treatment course. 2 It is administered intravenously.

[0102] The immune checkpoint inhibitor is administered to an adult at a dose of 2 to 10 mg / kg or 50 to 1200 mg once every 2 to 3 weeks. In a specific embodiment, the immune checkpoint inhibitor is administered to an adult at a dose of 3 to 10 mg / kg or 100 to 1200 mg once every 2 to 3 weeks.

[0103] All technical and scientific terms used that are not specifically defined herein have the meaning commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0104] In some embodiments, the present disclosure also discloses: 1. A FAK inhibitor, a microtubule inhibitor and an immune checkpoint inhibitor for use in a method for treating a tumor in a subject. 2. The FAK inhibitor is IN10018, defactinib, GSK2256098, PF-00562271, VS-4718, APG-2449, AMP945, AMP886, or a pharmaceutically acceptable salt thereof; or IN10018, defactinib, AMP945, or a pharmaceutically acceptable salt thereof; and alternatively IN10018, or a pharmaceutically acceptable salt thereof, or IN10018 tartrate, wherein the structure of IN10018 is:

[0105] [ka]

[0106] 2. The FAK inhibitor, microtubule inhibitor and immune checkpoint inhibitor of embodiment 1, wherein 3. The FAK inhibitor, microtubule inhibitor and immune checkpoint inhibitor according to embodiment 1 or 2, wherein the microtubule inhibitor is a taxane, eribulin, ixempera or a vinca alkaloid. 4. The FAK inhibitor, microtubule inhibitor and immune checkpoint inhibitor according to any one of embodiments 1 to 3, wherein the microtubule inhibitor is a taxane. 5. The FAK inhibitor, microtubule inhibitor and immune checkpoint inhibitor according to embodiment 3 or 4, wherein the taxane is docetaxel, paclitaxel, cabazitaxel or cephalomannine, or is docetaxel or paclitaxel. 6. The FAK inhibitor, microtubule inhibitor and immune checkpoint inhibitor according to any one of embodiments 1 to 5, wherein the microtubule inhibitor is docetaxel. 7. The FAK inhibitor, microtubule inhibitor and immune checkpoint inhibitor according to any one of embodiments 1 to 5, wherein the microtubule inhibitor is paclitaxel. 8. The FAK inhibitor, microtubule inhibitor and immune checkpoint inhibitor according to any one of embodiments 1 to 4, wherein the microtubule inhibitor is eribulin. 9. The FAK inhibitor, microtubule inhibitor and immune checkpoint inhibitor according to any one of embodiments 1 to 8, wherein the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, a PD-1 / PD-L1 small molecule inhibitor or a TIGIT inhibitor. 10. The FAK inhibitor, microtubule inhibitor and immune checkpoint inhibitor of any one of embodiments 1 to 9, wherein the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, optionally wherein the anti-PD-1 / PD-L1 antibody is pembrolizumab, tislelizumab, nivolumab, toripalimab, atezolizumab, durvalumab, avelumab, camrelizumab, sintilimab, cemiplimab, embafolimab, BMS-936559, JS003, SHR-1316, GS-4224, AN-4005, or MX-10181. 11. The FAK inhibitor, microtubule inhibitor and immune checkpoint inhibitor of any one of embodiments 1 to 9, wherein the immune checkpoint inhibitor is a PD-1 / PD-L1 small molecule inhibitor, optionally wherein the PD-1 / PD-L1 small molecule inhibitor is INCB-086550, lazertinib, IMMH-010, CA-170, ABSK043 or RRx-001. 12. The FAK inhibitor, microtubule inhibitor and immune checkpoint inhibitor according to any one of embodiments 1 to 9, wherein the immune checkpoint inhibitor is a TIGIT inhibitor, optionally wherein the TIGIT inhibitor is osipellimab (BGB-A1217), vibostolimab, domvanalimab (AB154), tiragolumab, berlestog, etigilimab, ONO-4686, JS-006, AZD-2936, HLX-301, SEA-TGT, M-6223, IBI-939, COM-902, AB-308, AGEN-1777, AK-127, BAT-6021, BAT-6005, ASP-8374, PM-1022, BMS-986207, HB0036 or IBI-321. 13. The FAK inhibitor, microtubule inhibitor, and immune checkpoint inhibitor according to embodiment 1, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the microtubule inhibitor is docetaxel, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor; or alternatively, the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the microtubule inhibitor is docetaxel, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody. 14. The FAK inhibitor, microtubule inhibitor, and immune checkpoint inhibitor of embodiment 1, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the microtubule inhibitor is paclitaxel, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor; or alternatively, the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the microtubule inhibitor is paclitaxel, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody. 15. The FAK inhibitor, microtubule inhibitor and immune checkpoint inhibitor according to any one of embodiments 1 to 14, wherein the FAK inhibitor, microtubule inhibitor and immune checkpoint inhibitor are administered to the subject simultaneously or sequentially. 16. Metastases caused by tumors including bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer, liver cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma, myeloma, rhabdomyosarcoma, inflammatory myofibroblastoma, neuroblastoma, pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), gastric cancer, testicular cancer, thyroid cancer, uterine cancer, mesothelioma, cholangiocarcinoma, leiomyosarcoma, liposarcoma, nasopharyngeal carcinoma, neuroendocrine carcinoma, ovarian cancer, salivary gland cancer, spindle cell carcinoma, anaplastic large cell lymphoma, and anaplastic thyroid gland cancer. 16. The FAK inhibitor, microtubule inhibitor and immune checkpoint inhibitor according to any one of embodiments 1 to 15, wherein the tumor is cancer, non-Hodgkin's lymphoma, Hodgkin's lymphoma, glioma or hematological malignancy, such as acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL) or chronic myelogenous leukemia (CML); or the tumor is breast cancer, ovarian cancer, colon cancer (including colorectal cancer), lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma or pancreatic cancer. 17. The FAK inhibitor, microtubule inhibitor and immune checkpoint inhibitor according to any one of embodiments 1 to 16, wherein the tumor is breast cancer, ovarian cancer or colon cancer (including colorectal cancer). 18.(a) FAK inhibitors, (b) microtubule inhibitors and (c) A kit or a pharmaceutically acceptable composition comprising an immune checkpoint inhibitor. 19. The FAK inhibitor is IN10018, defactinib, GSK2256098, PF-00562271, VS-4718, APG-2449, AMP945, AMP886 or a pharmaceutically acceptable salt thereof; alternatively, the FAK inhibitor is IN10018, defactinib, AMP945 or a pharmaceutically acceptable salt thereof; and further alternatively, the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof; or alternatively, the FAK inhibitor is IN10018 tartrate, and IN10018 is

[0107] [ka]

[0108] 19. The kit or composition of embodiment 18, having the structure: 20. The kit or composition according to embodiment 18 or 19, wherein the microtubule inhibitor is a taxane, eribulin, ixempera or vinca alkaloid. 21. The kit or composition according to any one of embodiments 18 to 20, wherein the microtubule inhibitor is a taxane. 22. The kit or composition according to embodiment 20 or 21, wherein the taxane is docetaxel, paclitaxel, cabazitaxel or cephalomannine, or is docetaxel or paclitaxel. 23. The kit or composition according to any one of embodiments 18 to 22, wherein the microtubule inhibitor is docetaxel. 24. The kit or composition according to any one of embodiments 18 to 22, wherein the microtubule inhibitor is paclitaxel. 25. The kit or composition according to any one of embodiments 18 to 22, wherein the microtubule inhibitor is eribulin. 26. The kit or composition of any one of embodiments 18 to 25, wherein the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, a PD-1 / PD-L1 small molecule inhibitor, or a TIGIT inhibitor. 27. The kit or composition of any one of embodiments 18 to 26, wherein the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, optionally wherein the anti-PD-1 / PD-L1 antibody is pembrolizumab, tislelizumab, nivolumab, toripalimab, atezolizumab, durvalumab, avelumab, camrelizumab, sintilimab, cemiplimab, embafolimab, BMS-936559, JS003, SHR-1316, GS-4224, AN-4005, or MX-10181. 28. The kit or composition of any one of embodiments 18-26, wherein the immune checkpoint inhibitor is a PD-1 / PD-L1 small molecule inhibitor, optionally wherein the PD-1 / PD-L1 small molecule inhibitor is INCB-086550, lazertinib, IMMH-010, CA-170, ABSK043, or RRx-001. 29. The kit or composition of any one of embodiments 18 to 26, wherein the immune checkpoint inhibitor is a TIGIT inhibitor, optionally wherein the TIGIT inhibitor is osipellimab (BGB-A1217), vibostolimab, domvanalimab (AB154), tiragolumab, berlestog, etigilimab, ONO-4686, JS-006, AZD-2936, HLX-301, SEA-TGT, M-6223, IBI-939, COM-902, AB-308, AGEN-1777, AK-127, BAT-6021, BAT-6005, ASP-8374, PM-1022, BMS-986207, HB0036, or IBI-321. 30. The kit or composition of embodiment 18, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the microtubule inhibitor is docetaxel, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor; or wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the microtubule inhibitor is docetaxel, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody. 31. The kit or composition of embodiment 18, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the microtubule inhibitor is paclitaxel, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor; or wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the microtubule inhibitor is paclitaxel, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody. 32. The kit or composition according to any one of embodiments 18 to 31, wherein the kit or composition is used as a medicament. 33. The medicament is used to treat tumors, and the tumors are caused by bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer, liver cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma, myeloma, rhabdomyosarcoma, inflammatory myofibroblastoma, neuroblastoma, pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), stomach cancer, testicular cancer, thyroid cancer, uterine cancer, mesothelioma, cholangiocarcinoma, leiomyosarcoma, liposarcoma, nasopharyngeal cancer, neuroendocrine carcinoma, ovarian cancer, salivary gland cancer, or spindle cell carcinoma. 33. The kit or composition of embodiment 32, wherein the tumor is a tumor of the breast, ovarian, colon (including colorectal), lung (including small cell lung cancer and non-small cell lung cancer), melanoma, or pancreatic cancer, including metastasis due to leukemia, anaplastic large cell lymphoma, anaplastic thyroid carcinoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, glioma, or hematological malignancy, such as acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), or chronic myelogenous leukemia (CML). 34. The kit or composition of embodiment 33, wherein the tumor is breast cancer, ovarian cancer or colon cancer (including colorectal cancer). 35. A method for treating a tumor in a subject, comprising administering to the subject therapeutically effective amounts of a FAK inhibitor, a microtubule inhibitor, and an immune checkpoint inhibitor. 36. The FAK inhibitor is IN10018, defactinib, GSK2256098, PF-00562271, VS-4718, APG-2449, AMP945, AMP886 or a pharmaceutically acceptable salt thereof; alternatively, the FAK inhibitor is IN10018, defactinib, AMP945 or a pharmaceutically acceptable salt thereof; and further alternatively, the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof; or alternatively, the FAK inhibitor is IN10018 tartrate, and IN10018 is

[0109] [ka]

[0110] 36. The method of embodiment 35, having the structure: 37. The method of embodiment 35 or 36, wherein the microtubule inhibitor is a taxane, eribulin, ixempera, or vinca alkaloid. 38. The method of any one of embodiments 35-37, wherein the microtubule inhibitor is a taxane. 39. The method of embodiment 37 or 38, wherein the taxane is docetaxel, paclitaxel, cabazitaxel or cephalomannine, or is docetaxel or paclitaxel. 40. The method of any one of embodiments 35-39, wherein the microtubule inhibitor is docetaxel. 41. The method of any one of embodiments 35-39, wherein the microtubule inhibitor is paclitaxel. 42. The method of any one of embodiments 35-37, wherein the microtubule inhibitor is eribulin. 43. The method of any one of embodiments 35-42, wherein the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, a PD-1 / PD-L1 small molecule inhibitor, or a TIGIT inhibitor. 44. The method of any one of embodiments 35-43, wherein the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, optionally wherein the anti-PD-1 / PD-L1 antibody is pembrolizumab, tislelizumab, nivolumab, toripalimab, atezolizumab, durvalumab, avelumab, camrelizumab, sintilimab, cemiplimab, embafolimab, BMS-936559, JS003, SHR-1316, GS-4224, AN-4005, or MX-10181. 45. The method of any one of embodiments 35-43, wherein the immune checkpoint inhibitor is a PD-1 / PD-L1 small molecule inhibitor, optionally wherein the PD-1 / PD-L1 small molecule inhibitor is INCB-086550, lazertinib, IMMH-010, CA-170, ABSK043, or RRx-001. 46. ​​The method of any one of embodiments 35 to 43, wherein the immune checkpoint inhibitor is a TIGIT inhibitor, optionally wherein the TIGIT inhibitor is osipellimab (BGB-A1217), vibostolimab, domvanalimab (AB154), tiragolumab, berlestog, etigilimab, ONO-4686, JS-006, AZD-2936, HLX-301, SEA-TGT, M-6223, IBI-939, COM-902, AB-308, AGEN-1777, AK-127, BAT-6021, BAT-6005, ASP-8374, PM-1022, BMS-986207, HB0036, or IBI-321. 47. The method of embodiment 35, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the microtubule inhibitor is docetaxel, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor; or wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the microtubule inhibitor is docetaxel, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody. 48. The method of embodiment 35, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the microtubule inhibitor is paclitaxel, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor; or wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the microtubule inhibitor is paclitaxel, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody. 49. The method of any one of embodiments 35 to 48, wherein the FAK inhibitor, microtubule inhibitor and immune checkpoint inhibitor are administered to the subject simultaneously or sequentially. 50. Metastases caused by tumors including bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer, liver cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma, myeloma, rhabdomyosarcoma, inflammatory myofibroblastoma, neuroblastoma, pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), gastric cancer, testicular cancer, thyroid cancer, uterine cancer, mesothelioma, cholangiocarcinoma, leiomyosarcoma, liposarcoma, nasopharyngeal carcinoma, neuroendocrine carcinoma, ovarian cancer, salivary gland cancer, and spindle cell carcinoma, undifferentiated large cell carcinoma 50. The method of any one of embodiments 35 to 49, wherein the tumor is follicular lymphoma, anaplastic thyroid carcinoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, glioma, or a hematological malignancy, such as acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), or chronic myelogenous leukemia (CML); or wherein the tumor is breast cancer, ovarian cancer, colon cancer (including colorectal cancer), lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma, or pancreatic cancer. 51. The method of any one of embodiments 35 to 50, wherein the tumor is breast cancer, ovarian cancer or colon cancer (including colorectal cancer). 52. A FAK inhibitor, a microtubule inhibitor and an immune checkpoint inhibitor for use in a method for treating a tumor by enhancing immunogenic cell death in a subject. 53. The FAK inhibitor is IN10018, defactinib, GSK2256098, PF-00562271, VS-4718, APG-2449, AMP945, AMP886, or a pharmaceutically acceptable salt thereof; alternatively, the FAK inhibitor is IN10018, defactinib, AMP945, or a pharmaceutically acceptable salt thereof; and further alternatively, the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof; or the FAK inhibitor is IN10018 tartrate, and IN10018 is

[0111] [ka]

[0112] 53. The FAK inhibitor, microtubule inhibitor, and immune checkpoint inhibitor of embodiment 52, having the structure: 54. The FAK inhibitor, microtubule inhibitor and immune checkpoint inhibitor according to embodiment 52 or 53, wherein the microtubule inhibitor is a taxane, eribulin, ixempera or a vinca alkaloid. 55. The FAK inhibitor, microtubule inhibitor and immune checkpoint inhibitor according to any one of embodiments 52 to 54, wherein the microtubule inhibitor is a taxane. 56. The FAK inhibitor, microtubule inhibitor and immune checkpoint inhibitor according to embodiment 54 or 55, wherein the taxane is docetaxel, paclitaxel, cabazitaxel or cephalomannine, or is docetaxel or paclitaxel. 57. The FAK inhibitor, microtubule inhibitor and immune checkpoint inhibitor according to any one of embodiments 52-56, wherein the microtubule inhibitor is docetaxel. 58. The FAK inhibitor, microtubule inhibitor and immune checkpoint inhibitor according to any one of embodiments 52-56, wherein the microtubule inhibitor is paclitaxel. 59. The FAK inhibitor, microtubule inhibitor and immune checkpoint inhibitor according to any one of embodiments 52-54, wherein the microtubule inhibitor is eribulin. 60. The FAK inhibitor, microtubule inhibitor and immune checkpoint inhibitor according to any one of embodiments 52 to 59, wherein the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, a PD-1 / PD-L1 small molecule inhibitor or a TIGIT inhibitor. 61. The FAK inhibitor, microtubule inhibitor and immune checkpoint inhibitor according to any one of embodiments 52 to 60, wherein the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, optionally wherein the anti-PD-1 / PD-L1 antibody is pembrolizumab, tislelizumab, nivolumab, toripalimab, atezolizumab, durvalumab, avelumab, camrelizumab, sintilimab, cemiplimab, embafolimab, BMS-936559, JS003, SHR-1316, GS-4224, AN-4005 or MX-10181. 62. The FAK inhibitor, microtubule inhibitor and immune checkpoint inhibitor according to any one of embodiments 52 to 60, wherein the immune checkpoint inhibitor is a PD-1 / PD-L1 small molecule inhibitor, optionally the PD-1 / PD-L1 small molecule inhibitor is INCB-086550, lazertinib, IMMH-010, CA-170, ABSK043 or RRx-001. 63. The FAK inhibitor, microtubule inhibitor and immune checkpoint inhibitor according to any one of embodiments 52 to 60, wherein the immune checkpoint inhibitor is a TIGIT inhibitor, optionally wherein the TIGIT inhibitor is osipellimab (BGB-A1217), vibostolimab, domvanalimab (AB154), tiragolumab, berlestog, etigilimab, ONO-4686, JS-006, AZD-2936, HLX-301, SEA-TGT, M-6223, IBI-939, COM-902, AB-308, AGEN-1777, AK-127, BAT-6021, BAT-6005, ASP-8374, PM-1022, BMS-986207, HB0036 or IBI-321. 64. The FAK inhibitor, microtubule inhibitor, and immune checkpoint inhibitor according to embodiment 52, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the microtubule inhibitor is docetaxel, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor; or wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the microtubule inhibitor is docetaxel, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody. 65. The FAK inhibitor, microtubule inhibitor, and immune checkpoint inhibitor according to embodiment 52, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the microtubule inhibitor is paclitaxel, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor; or wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the microtubule inhibitor is paclitaxel, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody. 66. The FAK inhibitor, microtubule inhibitor and immune checkpoint inhibitor according to any one of embodiments 52 to 65, wherein the FAK inhibitor, microtubule inhibitor and immune checkpoint inhibitor are administered to the subject simultaneously or sequentially. 67. Metastases caused by tumors including bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer, liver cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma, myeloma, rhabdomyosarcoma, inflammatory myofibroblastoma, neuroblastoma, pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), gastric cancer, testicular cancer, thyroid cancer, uterine cancer, mesothelioma, cholangiocarcinoma, leiomyosarcoma, liposarcoma, nasopharyngeal carcinoma, neuroendocrine carcinoma, ovarian cancer, salivary gland cancer, spindle cell carcinoma, anaplastic large cell lymphoma, anaplastic thyroid gland cancer 67. The FAK inhibitor, microtubule inhibitor and immune checkpoint inhibitor according to any one of embodiments 52 to 66, wherein the tumor is cancer, non-Hodgkin's lymphoma, Hodgkin's lymphoma, glioma or hematological malignancy, such as acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL) or chronic myelogenous leukemia (CML); or the tumor is breast cancer, ovarian cancer, colon cancer (including colorectal cancer), lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma or pancreatic cancer. 68. The FAK inhibitor, microtubule inhibitor and immune checkpoint inhibitor according to any one of embodiments 52 to 67, wherein the tumor is breast cancer, ovarian cancer or colon cancer (including colorectal cancer). 69. A method for treating a tumor by enhancing immunogenic cell death in a subject, comprising administering to the subject therapeutically effective amounts of a FAK inhibitor, a microtubule inhibitor, and an immune checkpoint inhibitor. 70. The FAK inhibitor is IN10018, defactinib, GSK2256098, PF-00562271, VS-4718, APG-2449, AMP945, AMP886, or a pharmaceutically acceptable salt thereof; alternatively, the FAK inhibitor is IN10018, defactinib, AMP945, or a pharmaceutically acceptable salt thereof; and further alternatively, the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof; or the FAK inhibitor is IN10018 tartrate, and IN10018 is

[0113] [ka]

[0114] 70. The method of embodiment 69, having the structure: 71. The method of embodiment 69 or 70, wherein the microtubule inhibitor is a taxane, eribulin, ixempera, or vinca alkaloid. 72. The method of any one of embodiments 69-71, wherein the microtubule inhibitor is a taxane. 73. The method of embodiment 71 or 72, wherein the taxane is docetaxel, paclitaxel, cabazitaxel or cephalomannine, or is docetaxel or paclitaxel. 74. The method of any one of embodiments 69-73, wherein the microtubule inhibitor is docetaxel. 75. The method of any one of embodiments 69-73, wherein the microtubule inhibitor is paclitaxel. 76. The method of any one of embodiments 69-73, wherein the microtubule inhibitor is eribulin. 77. The method of any one of embodiments 69 to 76, wherein the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, a PD-1 / PD-L1 small molecule inhibitor, or a TIGIT inhibitor. 78. The method of any one of embodiments 69-77, wherein the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, optionally wherein the anti-PD-1 / PD-L1 antibody is pembrolizumab, tislelizumab, nivolumab, toripalimab, atezolizumab, durvalumab, avelumab, camrelizumab, sintilimab, cemiplimab, embafolimab, BMS-936559, JS003, SHR-1316, GS-4224, AN-4005, or MX-10181. 79. The method of any one of embodiments 69-77, wherein the immune checkpoint inhibitor is a PD-1 / PD-L1 small molecule inhibitor, optionally wherein the PD-1 / PD-L1 small molecule inhibitor is INCB-086550, lazertinib, IMMH-010, CA-170, ABSK043, or RRx-001. 80. The method of any one of embodiments 69 to 77, wherein the immune checkpoint inhibitor is a TIGIT inhibitor, and optionally the TIGIT inhibitor is osipellimab (BGB-A1217), vibostolimab, domvanalimab (AB154), tiragolumab, berlestog, etigilimab, ONO-4686, JS-006, AZD-2936, HLX-301, SEA-TGT, M-6223, IBI-939, COM-902, AB-308, AGEN-1777, AK-127, BAT-6021, BAT-6005, ASP-8374, PM-1022, BMS-986207, HB0036, or IBI-321. 81. The method of embodiment 69, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the microtubule inhibitor is docetaxel, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor; or wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the microtubule inhibitor is docetaxel, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody. 82. The method of embodiment 69, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the microtubule inhibitor is paclitaxel, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor; or wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the microtubule inhibitor is paclitaxel, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody. 83. The method of any one of embodiments 69 to 82, wherein the FAK inhibitor, microtubule inhibitor and immune checkpoint inhibitor are administered to the subject simultaneously or sequentially. 84. Metastases caused by tumors including bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer, liver cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma, myeloma, rhabdomyosarcoma, inflammatory myofibroblastoma, neuroblastoma, pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), gastric cancer, testicular cancer, thyroid cancer, uterine cancer, mesothelioma, cholangiocarcinoma, leiomyosarcoma, liposarcoma, nasopharyngeal carcinoma, neuroendocrine carcinoma, ovarian cancer, salivary gland cancer, and spindle cell carcinoma, undifferentiated large cell carcinoma 84. The method of any one of embodiments 69 to 83, wherein the tumor is follicular lymphoma, anaplastic thyroid carcinoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, glioma, or a hematological malignancy, such as acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), or chronic myelogenous leukemia (CML); or wherein the tumor is breast cancer, ovarian cancer, colon cancer (including colorectal cancer), lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma, or pancreatic cancer. 85. The method of any one of embodiments 69-84, wherein the tumor is breast cancer, ovarian cancer, or colon cancer (including colorectal cancer). 86. Use of a FAK inhibitor in the manufacture of a medicament for treating a tumor in a subject, wherein a FAK inhibitor, a microtubule inhibitor, and an immune checkpoint inhibitor are administered to the subject. 87. Use of a microtubule inhibitor in the manufacture of a medicament for treating a tumor in a subject, wherein a FAK inhibitor, a microtubule inhibitor and an immune checkpoint inhibitor are administered to the subject. 88. Use of an immune checkpoint inhibitor in the manufacture of a medicament for treating a tumor in a subject, wherein a FAK inhibitor, a microtubule inhibitor and an immune checkpoint inhibitor are administered to the subject. 89. Use of a FAK inhibitor, a microtubule inhibitor and an immune checkpoint inhibitor in the manufacture of a combination pharmaceutical for treating a tumor. 90. Use of a FAK inhibitor in the manufacture of a combination medicament for treating a tumor with a microtubule inhibitor and an immune checkpoint inhibitor. 91. Use of a microtubule inhibitor in the manufacture of a combination medicament for treating a tumor with a FAK inhibitor and an immune checkpoint inhibitor. 92. Use of an immune checkpoint inhibitor in the manufacture of a combination medicament for treating a tumor, together with a FAK inhibitor and a microtubule inhibitor. 93. Use of a FAK inhibitor, a microtubule inhibitor and an immune checkpoint inhibitor in the manufacture of a medicament for the combined treatment of a tumor. 94. Use of a FAK inhibitor in the manufacture of a medicament for the combined treatment of a tumor with a microtubule inhibitor and an immune checkpoint inhibitor. 95. Use of a microtubule inhibitor in the manufacture of a medicament for the combined treatment of a tumor with a FAK inhibitor and an immune checkpoint inhibitor. 96. Use of an immune checkpoint inhibitor in the manufacture of a medicament for the combined treatment of a tumor with a FAK inhibitor and a microtubule inhibitor. 97. The FAK inhibitor is IN10018, defactinib, GSK2256098, PF-00562271, VS-4718, APG-2449, AMP945, AMP886 or a pharmaceutically acceptable salt thereof, or IN10018, defactinib, AMP945 or a pharmaceutically acceptable salt thereof, and further alternatively IN10018 or a pharmaceutically acceptable salt thereof, or IN10018 tartrate, wherein the structure of IN10018 is

[0115] [ka]

[0116] The use according to any one of embodiments 86 to 96, wherein 98. The use according to any one of embodiments 86 to 97, wherein the microtubule inhibitor is a taxane, eribulin, ixempera or a vinca alkaloid. 99. The use according to any one of embodiments 86 to 98, wherein the microtubule inhibitor is a taxane. 100. The use according to embodiment 98 or 99, wherein the taxane is docetaxel, paclitaxel, cabazitaxel or cephalomannine, or is docetaxel or paclitaxel. 101. The use according to any one of embodiments 98 to 100, wherein the microtubule inhibitor is docetaxel. 102. The use according to any one of embodiments 98 to 100, wherein the microtubule inhibitor is paclitaxel. 103. The use according to any one of embodiments 98-100, wherein the microtubule inhibitor is eribulin. 104. The use according to any one of embodiments 98 to 103, wherein the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, a PD-1 / PD-L1 small molecule inhibitor, or a TIGIT inhibitor. 105. The use of any one of embodiments 98 to 104, wherein the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, optionally wherein the anti-PD-1 / PD-L1 antibody is pembrolizumab, tislelizumab, nivolumab, toripalimab, atezolizumab, durvalumab, avelumab, camrelizumab, sintilimab, cemiplimab, embafolimab, BMS-936559, JS003, SHR-1316, GS-4224, AN-4005, or MX-10181. 106. The use of any one of embodiments 98 to 104, wherein the immune checkpoint inhibitor is a PD-1 / PD-L1 small molecule inhibitor, optionally wherein the PD-1 / PD-L1 small molecule inhibitor is INCB-086550, lazertinib, IMMH-010, CA-170, ABSK043, or RRx-001. 107. The use according to any one of embodiments 98 to 104, wherein the immune checkpoint inhibitor is a TIGIT inhibitor, optionally wherein the TIGIT inhibitor is osipellimab (BGB-A1217), vibostolimab, domvanalimab (AB154), tiragolumab, berlestog, etigilimab, ONO-4686, JS-006, AZD-2936, HLX-301, SEA-TGT, M-6223, IBI-939, COM-902, AB-308, AGEN-1777, AK-127, BAT-6021, BAT-6005, ASP-8374, PM-1022, BMS-986207, HB0036 or IBI-321. 108. The use of any one of embodiments 98 to 107, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the microtubule inhibitor is docetaxel, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor; or alternatively, the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the microtubule inhibitor is docetaxel, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody. 109. The use of any one of embodiments 98 to 107, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the microtubule inhibitor is paclitaxel, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor; or alternatively, the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the microtubule inhibitor is paclitaxel, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody. 110. The use according to any one of embodiments 98 to 109, wherein the FAK inhibitor, the microtubule inhibitor and the immune checkpoint inhibitor are administered to the subject simultaneously or sequentially. 111. Metastases caused by tumors including bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer, liver cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma, myeloma, rhabdomyosarcoma, inflammatory myofibroblastoma, neuroblastoma, pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), gastric cancer, testicular cancer, thyroid cancer, uterine cancer, mesothelioma, cholangiocarcinoma, leiomyosarcoma, liposarcoma, nasopharyngeal cancer, neuroendocrine carcinoma, ovarian cancer, salivary gland cancer, and spindle cell carcinoma, undifferentiated large cell carcinoma The use according to any one of embodiments 86 to 110, wherein the tumor is follicular lymphoma, anaplastic thyroid carcinoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, glioma or a hematological malignancy, such as acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL) or chronic myelogenous leukemia (CML); or the tumor is breast cancer, ovarian cancer, colon cancer (including colorectal cancer), lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma or pancreatic cancer. 112. The use according to any one of embodiments 98 to 111, wherein the tumor is breast cancer, ovarian cancer or colon cancer (including colorectal cancer). [Example]

[0117] The following examples are presented to further illustrate the present disclosure. It should be understood that these examples are used only to illustrate the present disclosure and are not intended to limit the scope of the present disclosure.

[0118] Assay methods without specific conditions in the following examples can be carried out according to conventional conditions for this type of reaction or according to conditions suggested by the manufacturer. All assay materials and reagents used in the following examples are commercially available unless otherwise specified.

[0119] The abbreviations used in the examples have the following meanings:

[0120] [Table 1A]

[0121] [Table 1B]

[0122] Example 1 Enhancement of immunogenic cell death in ovarian cancer cells in response to docetaxel by targeting FAK Assay Protocol: 1. FAK silencing in combination with docetaxel promotes apoptosis in ovarian cancer cells HCC827

[0123] siRNA technology was used in an in vitro assay to reduce FAK expression levels and combine it with docetaxel for 48 hours; flow cytometry was used to detect apoptosis in control (DMSO) and FAK-silenced cells.

[0124] 2. FAK silencing in combination with docetaxel can efficiently promote the development of ICD in ovarian cancer cells SK-OV-3

[0125] They used siRNA technology in an in vitro assay to reduce FAK expression levels and combined it with docetaxel for 48 hours, and used flow cytometry to detect the expression of calreticulin, a primary target of ICD.

[0126] Assay antibodies: recombinant Alexa Fluor® 647 fluorescent anti-calreticulin antibody (Abcam, ab196159), Annexin V Apoptosis Detection Kit (Invitrogen, A35110).

[0127] FAK siRNA was provided by Gene Pharma and the sequence is shown in the table below: F:CCUGUAUGCCUAUCAGCUUTT; R:AAGCUGAUAGGCAUACAGGTT

[0128] Assay equipment: Fluorescence microscope (Olympus U-HGLGPS). Chemiluminescence imager (BIORAD chemidoc touch).

[0129] Assay Results: 1. FAK silencing in combination with docetaxel significantly enhanced apoptosis in SK-OV-3 cells. SK-OV-3 cells were transfected with control siRNA or FAK siRNA at a final concentration of 50 nM. 24 hours after transfection, the cells were treated with 0.3 μM or 1 μM docetaxel for 48 hours. Cells were stained using an Annexin V kit and detected by flow cytometry. Apoptosis values ​​were counted, compared with those of the control group, and plotted using Graphpad 8.0. The results showed that apoptosis in the FAK-silenced group was significantly enhanced after docetaxel treatment compared with the control group, as shown in Figure 1.

[0130] 2. Combining FAK silencing with docetaxel significantly enhanced the release and exposure of calreticulin targeted by ICD.

[0131] SK-OV-3 cells were transfected with control siRNA or FAK siRNA at a final concentration of 50 nM. 24 hours after transfection, the cells were treated with 1 μM docetaxel for 48 hours. The cells were fluorescently stained with calreticulin antibody, and the staining results were analyzed by flow cytometry. Results from FlowJo software showed that after FAK silencing in combination with docetaxel, the release and exposure of calreticulin were significantly enhanced, as shown in Figure 2.

[0132] Example 2 Enhancement of immunogenic cell death in breast cancer cells in response to eribulin by targeting FAK inhibition Assay Protocol: 1. FAK silencing in combination with eribulin promotes apoptosis in breast cancer cells MDA-MB-231

[0133] siRNA technology was used in an in vitro assay to reduce the expression level of FAK and combined with eribulin for 48 hours; flow cytometry was used to detect apoptosis in control and FAK-silenced cells.

[0134] 2. FAK silencing in combination with eribulin can efficiently promote the development of ICD in breast cancer cells MDA-MB-231

[0135] They used siRNA technology in an in vitro assay to reduce FAK expression levels and combined it with eribulin for 48 hours, and used flow cytometry to detect the expression of calreticulin, a primary target of ICD.

[0136] Assay antibody: Recombinant Alexa Fluor® 647 fluorescent anti-calreticulin antibody (Abcam, ab196159), Annexin V Apoptosis Detection Kit (Invitrogen, A35110).

[0137] FAK siRNA was provided by Gene Pharma and the sequence is shown in the table below: F:CCUGUAUGCCUAUCAGCUUTT; R:AAGCUGAUAGGCAUACAGGTT Assay equipment: Fluorescence microscope (Olympus U-HGLGPS) and chemiluminescence imager (BIORAD chemidoc touch).

[0138] Assay Results: 1. FAK silencing combined with eribulin significantly enhanced apoptosis in MDA-MB-231 cells. MDA-MB-231 cells were transfected with control siRNA or FAK siRNA at a final concentration of 50 nM. 24 hours after transfection, the cells were treated with 0.15 μM eribulin for 48 hours. The cells were stained using an Annexin V kit and detected by flow cytometry. The early and late apoptosis values ​​were counted and compared with those of the DMSO control group, and plotted using Graphpad 8.0. The results showed that, compared with the control group, early and late apoptosis in the FAK-silenced group was significantly enhanced after eribulin treatment, as shown in Figure 3.

[0139] 2. Combining FAK silencing with eribulin significantly enhanced the release and exposure of calreticulin, an ICD target.

[0140] MDA-MB-231 cells were transfected with control siRNA or FAK siRNA at a final concentration of 50 nM. 24 hours after transfection, the cells were treated with 0.15 μM eribulin for 48 hours. The cells were fluorescently stained with calreticulin antibody, and the staining results were analyzed by flow cytometry. Results from FlowJo software showed that after FAK silencing in combination with eribulin, the release and exposure of calreticulin were significantly enhanced, as shown in Figure 4.

[0141] Example 3 Synergistic effect of IN10018 and docetaxel in colon cancer CT26 cells CT26 cells were cultured in RPMI-1640 (Shanghai Basalmedia, Catalog Number: L210KJ, Batch Number: F210916) + 10% FBS (Gibco, Catalog Number: 10099-141c, Batch Number: 2158737cp) and passaged twice. If the cells were in good condition, they were seeded into a 96-well plate at 3,000 cells / well. After the cells were seeded for 24 hours, medium containing docetaxel was added. Ten drug concentrations were set up. The first concentration was 30 μM, which was serially diluted three-fold, with the last one being a control with zero drug concentration. Three compound wells were set up for each drug concentration. At the same time, another group of cells was established with the same drug concentrations as in the above method. The difference was that 5 μM IN10018 was added to each well, the drugs were mixed, and the plates were incubated at 37° C. in a 5% CO 2 incubator for 72 hours.

[0142] After 72 hours of drug action, the cells were observed under a microscope. 10 μl of CCK8 detection reagent (Cellorlab, Cat. No. CX001M, Batch No. 2571100) was added to each well, and the plate was incubated at 37°C in a 5% CO2 incubator for 2-4 hours. The plate was then read at OD450 using a microplate reader (chemiluminescence method).

[0143] The analysis results showed that the IC50 of the docetaxel group was 0.19 μM; the IC50 of the docetaxel + 5 μM IN10018 group was <0.005 μM. The IC50 of the group containing IN10018 was significantly lower than that of the group without IN10018, indicating that the efficacy of the two-drug combination treatment group was better than that of the single-drug treatment group, as shown in Figure 5.

[0144] Example 4 Studies on IN10018 and docetaxel in colon cancer CT26 cells CT26 cells (Institute of Cell Biology, Chinese Academy of Sciences) were cultured in RPMI-1640 (Shanghai Basalmedia, catalog number: L210KJ, batch number: F210916) plus 10% FBS (Gibco, catalog number: 10099-141c, batch number: 2158737cp) and passaged twice. If the cells were in good condition, they were placed in 24-well plates. 24 hours after cell seeding, four groups were established: Group 1 was the control group, to which medium was added; Group 2 was treated with 5 μM IN10018; Group 3 was treated with 0.1 μM docetaxel (MCE, catalog number: HY-B0011, batch number: 111613); and Group 4 was treated with a combination of IN10018 (5 μM) and docetaxel (0.1 μM). The drugs were mixed and the cells were cultured in a 5% CO2 incubator at 37°C for 48 hours.

[0145] After 48 hours of drug action, the cells were observed and photographed under a microscope. Photographs were saved. The cells were then collected for flow cytometry and washed twice with flow buffer (PBS + 2% FBS). 0.5 μl of AF647 anti-calreticulin antibody (Abcam, Catalog No.: ab196159, Batch No.: CR33676773) was added to each well and mixed thoroughly. The cells were incubated in the dark at 4°C for 20 minutes. After 20 minutes, the cells were washed twice with flow buffer (PBS + 2% FBS). A cell apoptosis detection kit (Beyotime, Catalog No.: CL062L, Batch No.: 021921210811) was used. 195 μl of Annexin-V-FITC conjugate solution was added and the cells were gently mixed. 5 μl of Annexin-V-FITC antibody was added and the mixture was gently mixed. 10 μl of PI dye was added and mixed. The mixture was incubated in the dark at room temperature for 15 minutes and then analyzed on a flow cytometer.

[0146] The cells were observed under a microscope. The cell condition of the docetaxel single-drug group and the two-drug combination group was poor. The two-drug combination group was the worst, showing more cell death. The cell condition of the control group and the IN10018 group was good. The results showed that the CRT positive rate and Annexin V positive rate of the two-drug combination group were higher than those of the single-drug groups, as shown in Figures 6, 7a, and 7b.

[0147] Example 5 Study on the induction of immunogenic cell death targets by eribulin and IN10018 in mouse mammary carcinoma 4T1 cells Compound information is shown in Table 1.

[0148] [Table 2]

[0149] The main reagent information for the assay is shown in Table 2.

[0150] [Table 3]

[0151] The assay design is shown in Table 3.

[0152] [Table 4]

[0153] Cell culture: 4T1 cells were cultured in vitro as monolayers in RPMI-1640 medium containing 10% fetal bovine serum at 37°C and 5% CO. Trypsin was used for routine digestion and passage two to three times per week. When cells were in the exponential growth phase and reached 80% to 90% adherent confluence, they were harvested and plated.

[0154] 4T1 cells were digested with trypsin, then collected and counted. Based on the counting results, the cells were diluted with RPMI-1640 + 10% FBS to a concentration of 50,000 cells per milliliter. The cells were then plated into a 12-well cell culture plate with 2 ml of cell suspension, i.e., 100,000 cells per well. After plating, the cells were cultured in a 37°C and 5% CO2 incubator.

[0155] Addition of compounds to be tested: 24 hours after plating, the test compounds IN10018 and eribulin were added to different wells, respectively. The group divisions and drug concentrations are shown in Table 3.

[0156] Cell collection for flow cytometry: After 48 hours of drug action, the cells were photographed using a microscope, then trypsinized and collected for flow cytometry staining.

[0157] The cells were washed twice with flow buffer (DPBS + 2% FBS), and each group of cells was divided into two equal portions. In one portion, 0.5 μl of AF647 anti-calreticulin antibody was added to each well and mixed. The cells were incubated in the dark at 4°C for 20 min. After washing once with flow buffer, 195 μl of Annexin-V-FITC conjugated solution was added. After gently mixing the cells, 5 μl of Annexin-V-FITC antibody was added. After thorough mixing, 1.0 μl of PI dye was added and mixed. The cells were incubated in the dark at room temperature for 15 min and then subjected to flow cytometry. In the other portion, 0.5 μl of CoraLite® 488-conjugated GRP94 polyclonal antibody was added to each well and mixed thoroughly. The cells were incubated in the dark at 4°C for 20 min, then washed twice with flow buffer and resuspended in 200 μl of flow buffer. The cells were then subjected to flow cytometry.

[0158] Data Analysis: After the assay, the cell positive rate was analyzed using Flowjo (V10) software.

[0159] Assay Results: After 48 hours of drug action, the cell status of each group was observed under a microscope. Cell death was evident in the eribulin monotherapy group, and the most significant cell death was in the combined drug group. The cell viability in the control group and IN10018 group was better. Flow cytometry analysis showed that the positive rates of CRT, Annexin-V, and GRP94 in the combined drug group were significantly higher than those in the single drug group. The relevant detection results are shown in Figures 8a, 8b, and 8c.

[0160] Example 6 In vitro study of the induction of immunogenic cell death targets by eribulin and IN10018 in mouse ovarian epithelial carcinoma ID8 cells and human ovarian epithelial carcinoma TOV-21G cells The compound and main reagent information are the same as those in Example 5.

[0161] The assay design is shown in Table 4.

[0162] [Table 5]

[0163] Cell culture: ID8 and TOV-21G cells were cultured in vitro in monolayers. ID8 cells were cultured in DMEM medium containing 10% fetal bovine serum. TOV-21G cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum. Both were cultured at 37°C in a 5% CO2 incubator. Trypsin was used for routine digestion and subculture two to three times a week. When cells were in the exponential growth phase and reached 80% to 90% adherent confluence, they were harvested and plated.

[0164] ID8 cells and TOV-21G cells were digested with trypsin, then collected and counted. Based on the counting results, the cells were diluted with the corresponding complete medium to a concentration of 50,000 cells per milliliter. The cells were then plated into 12-well cell culture plates with 2 ml of cell suspension, i.e., 100,000 cells per well.

[0165] After plating, the cells were cultured in a 37°C and 5% CO2 incubator.

[0166] Addition of compounds to be tested: 24 hours after plating, the test compounds IN10018 and eribulin were added to different wells, respectively. The group divisions and drug concentrations are shown in Table 4.

[0167] Cell collection for flow cytometry: After 48 hours of drug action, the cells were photographed using a microscope, then trypsinized and collected for flow cytometry staining.

[0168] The cells were washed twice with flow buffer (DPBS + 2% FBS). 0.5 μl of AF647 anti-calreticulin antibody was added to each well and mixed. The cells were incubated for 20 min at 4°C in the dark. After one wash with flow buffer, 195 μl of Annexin-V-FITC conjugate solution was added and the cells were gently mixed thoroughly. 5 μl of Annexin-V-FITC antibody was added. After further mixing, 10 μl of PI dye was added and mixed thoroughly. The cells were incubated for 15 min at room temperature in the dark. The cells were then subjected to flow cytometry.

[0169] Data Analysis: After the assay, the cell positive rate was analyzed using Flowjo (V10) software.

[0170] Assay Results: The cell status was observed under a microscope. In both cell lines, cell death was evident in the eribulin single-drug group, with the most significant cell death occurring in the combined drug group. The cell viability in the control and IN10018 groups was better. Flow cytometry analysis showed that the positive rates of CRT and Annexin V in the combined drug group were significantly higher than those in the single-drug groups. The assay results for the ID8 cell line are shown in Figures 9a and 9b, and the assay results for the TOV-21G cell line are shown in Figures 10a and 10b.

[0171] Example 7 In vitro study of the induction of immunogenic cell death targets by docetaxel / eribulin / paclitaxel and defactinib in murine colon cancer CT26 cells Compound information is shown in Table 5.

[0172] [Table 6]

[0173] The main reagent information for the assay is shown in Table 2:

[0174] The assay design is shown in Table 6:

[0175] [Table 7]

[0176] Cell culture: CT26 cells were cultured in vitro in monolayers in RPMI-1640 medium containing 10% fetal bovine serum at 37°C and 5% CO2. Trypsin was used for routine digestion and passage two to three times per week. When cells were in exponential growth phase and reached 80% to 90% adherent confluence, they were harvested and plated.

[0177] CT26 cells were digested with trypsin, then collected and counted. Based on the counting results, the cells were diluted with the corresponding complete medium to a concentration of 50,000 cells per milliliter. The cells were then plated into 12-well cell culture plates with 2 ml of cell suspension per well, i.e., 100,000 cells.

[0178] After plating, the cells were cultured in a 37°C and 5% CO2 incubator.

[0179] 24 hours after plating, the test compounds docetaxel, eribulin, paclitaxel, and defactinib were added to different wells, respectively. The groupings and drug concentrations are shown in Table 6.

[0180] After 48 hours of drug action, the cells were photographed using a microscope, then trypsinized and collected for flow cytometry staining.

[0181] Cells were washed twice with flow buffer (DPBS + 2% FBS). 0.5 μl of AF647 anti-calreticulin antibody was added to each well and mixed thoroughly. Cells were incubated for 20 min at 4°C in the dark. After one wash with flow buffer, 195 μl of Annexin-V-FITC conjugate solution was added and the cells were gently mixed thoroughly. 5 μl of Annexin-V-FITC antibody was added. After further mixing, 10 μl of PI dye was added and mixed thoroughly. Cells were incubated for 15 min at room temperature in the dark. Cells were then subjected to flow cytometry.

[0182] Data Analysis: After the assay, the cell positive rate was analyzed using Flowjo (V10) software.

[0183] Assay Results: This assay evaluated the effect of docetaxel / eribulin / paclitaxel alone and in combination with defactinib on inducing the expression of immune cell death targets in CT26 cells in vitro.

[0184] After 48 hours of drug action, the cell status in each group was observed under a microscope. Cell death became obvious in the docetaxel / eribulin / paclitaxel single-drug group, and cell death in the combined drug group was the most severe. Cell viability in the control group was better, while cell death in the defactinib single-drug group was more severe. Flow cytometry analysis showed that the CRT and Annexin V positivity rates in the combined drug group were significantly higher than those in the single-drug groups. The results of the docetaxel assay are shown in Figures 11a and 11b, the results of the eribulin assay are shown in Figures 12a and 12b, and the results of the paclitaxel assay are shown in Figures 13a and 13b.

[0185] Example 8 In vitro study of the induction of immunogenic cell death targets by docetaxel / eribulin and defactinib in murine breast cancer 4T1 cells The compound information is shown in Table 5 (without paclitaxel), and the main reagent information is shown in Table 2.

[0186] The assay design is shown in Table 7:

[0187] [Table 8]

[0188] Cell culture: 4T1 cells were cultured in vitro in monolayers in RPMI-1640 medium containing 10% fetal bovine serum at 37°C in a 5% CO2 incubator. Trypsin was used for routine digestion and passage two to three times per week. When cells were in the exponential growth phase and reached 80% to 90% adherent confluence, they were harvested and plated.

[0189] 4T1 cells were digested with trypsin, then harvested and counted. Based on the counting results, the cells were diluted with the corresponding complete medium to a concentration of 50,000 cells per milliliter. The cells were then plated into 12-well cell culture plates with 2 ml of cell suspension, i.e., 100,000 cells per well.

[0190] After plating, the cells were cultured in a 37°C and 5% CO2 incubator.

[0191] 24 hours after plating, the test compounds defactinib, docetaxel, and eribulin were added to different wells, respectively. The group divisions and drug concentrations are shown in Table 7.

[0192] Cell collection for flow cytometry: After 48 hours of drug action, the cells were photographed using a microscope, then trypsinized and collected for flow cytometry staining.

[0193] Cells were washed twice with flow buffer (DPBS + 2% FBS). 0.5 μl of AF647 anti-calreticulin antibody was added to each well and mixed thoroughly. Cells were incubated for 20 min at 4°C in the dark. After one wash with flow buffer, 195 μl of Annexin-V-FITC conjugate solution was added and the cells were gently mixed thoroughly. 5 μl of Annexin-V-FITC antibody was added. After further mixing, 10 μl of PI dye was added and mixed. Cells were incubated for 15 min at room temperature in the dark. Cells were then subjected to flow cytometry.

[0194] Data Analysis: After the assay, the cell positive rate was analyzed using Flowjo (V10) software.

[0195] Assay Results: After 48 hours of drug action, the cell status in each group was observed under a microscope. Cell death was evident in the docetaxel / eribulin monotherapy group, and cell death in the combined drug group was the most severe. Cell viability in the control group was better, while cell death in the defactinib monotherapy group was more severe. Flow cytometry analysis showed that the positive rates of CRT and Annexin V in the combined drug group were significantly higher than those in the single drug groups. The results of the docetaxel assay are shown in Figures 14a and 14b, and the results of the eribulin assay are shown in Figures 15a and 15b.

[0196] Example 9 Study on the in vivo antitumor effect of docetaxel injection in a subcutaneous allograft tumor model of breast cancer 4T1 cells in BALB / c mice Test materials: Mice: 6-8 week old female BALB / c mice were purchased from SHANGHAI SLAC LABORATORY ANIMAL CO. LTD. The assay began after the animals arrived and adapted to the assay environment. Animals were kept in IVC (Independently Ventilated System) cages (5 per cage) in an SPF animal room. All cages, padding, and drinking water must be sterilized before use. All assay personnel should wear protective clothing and latex gloves when working in the animal room. Cages, food, and drinking water were changed twice a week. The feeding environment and lighting conditions were as follows: Temperature: 20~26℃ Humidity: 40~70% Lighting period: 12 hours light, 12 hours no light Cage: Polycarbonate, 300mm x 180mm x 150mm. Padding was corncob, which was changed twice a week. Food: Assay animals were provided with food (irradiation sterilized dry pelleted food) ad libitum throughout the assay period. Drinking Water: Assay animals were given free access to sterile water. Cage Identification: The animal information card in each cage should indicate the number of animals in the cage, sex, strain, date of receipt, dosing regimen, assay number, assay group and start date. Animal Identification: Assay animals were identified by ear tags.

[0197] Compound information is shown in Table 8.

[0198] [Table 9]

[0199] Breast cancer cells 4T1 (supplied by Nanjing Cobioer Biotechnology Co., Ltd., catalog number: CBP60352) were maintained and passaged by INXMED (Nanjing) Co., Ltd. Cells were cultured in vitro in monolayers in RPMI-1640 medium containing 10% fetal bovine serum at 37°C in a 5% CO2 incubator. Trypsin-EDTA was used for routine digestion and passage two to three times per week. When cells were in the exponential growth phase and reached 80%-90% adherent confluence, they were harvested and plated.

[0200] Cell inoculation and grouping 2×10 5 0.1 mL of the cell suspension containing the cells was inoculated subcutaneously into the right dorsal surface of each mouse. 3 When tumor volume reached 10 days after cell inoculation, mice were randomly divided into groups for drug administration according to tumor volume. Group information is shown in Table 9.

[0201] [Table 10]

[0202] The formulations of the test articles are detailed in Table 10.

[0203] [Table 11]

[0204] Daily observation of assay animals Any modifications to the formulation and the assay protocol were reviewed and approved by ArrayBridge's IACUC. The use and welfare of the assay animals was carried out in accordance with AAALAC regulations. Animal health and mortality were monitored daily with routine checks that included tumor growth and the effect of drug treatment on the animals' daily behavior, such as activity, food and water consumption (estimated by visual inspection), changes in body weight, and observation of any physical signs or any other abnormalities. The number of animal deaths and side effects in each group was recorded based on the number of animals in each group.

[0205] Assay Stop If the animal's health condition continues to deteriorate or the tumor volume exceeds 3,000 mm 3 Euthanasia should be performed if the weight of the animal exceeds 2000 mm or if severe disease or pain is observed. The veterinarian was notified and euthanasia was performed in the following cases: obvious weight loss, i.e., weight loss of more than 20%; inability to eat and drink freely; mean tumor volume of the control group exceeding 2000 mm 3 The assay was terminated when the animal continued to deteriorate, showing the following signs: piloerection, hunched back, pale ears, nose, eyes or paws, rapid breathing, convulsions, persistent diarrhea, dehydration, slow movements, vocalization.

[0206] Tumor Measurements and Assay Parameters Tumor diameters were measured three times a week using calipers. Tumor volume was calculated using the formula: V = 0.5 × a × b 2 where a and b represent the long and short diameters of the tumor, respectively.

[0207] Based on the tumor volume on day 1 after grouping, the tumor growth inhibition rate (TGI) (%) was calculated according to the following formula: TGI (%) = [1 - (mean tumor volume of the treatment group - mean tumor volume of the treatment group at the beginning of treatment) / (mean tumor volume of the vehicle control group - mean tumor volume of the vehicle control group at the beginning of treatment)] × 100%.

[0208] statistical analysis Statistical analysis was performed using Prism Graphpad software and was based on tumor volume at the end of the assay. Comparisons between multiple groups were analyzed using two-way ANOVA and Fisher's LSD test. A P value of less than 0.05 was considered statistically significant.

[0209] Assay Results In vivo efficacy of test articles DTX and / or MAX10181 in combination with IN10018 in a BALB / c mouse subcutaneous allograft tumor model of 4T1 murine breast cancer cells. Tumor growth was monitored daily after cell inoculation. On day 10 post-inoculation, mice were divided into groups based on tumor volume. The mean tumor volume at enrollment was approximately 52 mm. 3 Due to tumor burden, animals in the control group were euthanized on day 31 post-inoculation, which was day 21 post-treatment according to group and the entire assay was terminated.

[0210] On day 21 after group-specific administration, the tumor volume in the control group was 2129.2 ± 322.0 mm 3 The tumor volumes in the DTX (10 mg / kg), MAX10181 (120 mg / kg), DTX + IN10018 (10 + 25 mg / kg), DTX + MAX10181 (10 + 120 mg / kg), and DTX + IN10018 + MAX10181 (10 + 25 + 120 mg / kg) treatment groups were 1818.7 ± 644.0 mm, respectively. 3 , 2205.7±912.7mm 3 , 1182.9±264.3mm 3 , 1480.3±345.6mm 3 and 829.4±249.1mm 3(See Table 11.) Compared with the control group, the tumor volumes in the DTX (10 mg / kg), MAX10181 (120 mg / kg), DTX + IN10018 (10 + 25 mg / kg), DTX + MAX10181 (10 + 120 mg / kg), and DTX + IN10018 + MAX10181 (10 + 25 + 120 mg / kg) groups showed tumor inhibition rates (TGI) of 14.9% (p = 0.0147), -3.7% (p = 0.5642), 45.6% (p < 0.0001), 31.3% (p < 0.0001), and 62.6% (p < 0.0001), respectively (See Table 11.). When the overall tumor volume was compared among the DTX + IN10018 + MAX10181 (10 + 25 + 120 mg / kg) triple-drug combination groups for statistical analysis, the P values ​​for the control group, DTX (10 mg / kg), MAX10181 (120 mg / kg), DTX + IN10018 (10 + 25 mg / kg), and DTX + MAX10181 (10 + 120 mg / kg) were p<0.0001, p<0.0001, p=0.0055, and p<0.0001, respectively. The tumor volumes of each treatment group at different times are shown in Figure 16.

[0211] [Table 12]

[0212] The assay was performed according to the administration regimen. During the assay, animal activity, such as eating and drinking, was observed daily, and animal weights were recorded three times a week. The animal weight curves are shown in Figure 17. During the entire administration cycle, animals in the MAX10181-related groups exhibited diarrhea, which caused the death of one animal each in G3 MAX10181 (120 mg / kg) and G5 DTX + MAX10181 (10 + 120 mg / kg). Furthermore, the body weight of DTX + IN10018 + MAX10181 (10 + 25 + 120 mg / kg) decreased, but the decrease did not exceed 10%; the animals in each group were in good mental and motor condition and tolerated the various administration modes.

[0213] conclusion Compared with the blank control group, the DTX (10 mg / kg), DTX + IN10018 (10 + 25 mg / kg), DTX + MAX10181 (10 + 120 mg / kg), and DTX + IN10018 + MAX10181 (10 + 25 + 120 mg / kg) treatment groups all showed significant tumor growth inhibitory effects, with statistically significant differences compared with the control group. Throughout the entire treatment period, the tumor volume in the DTX + IN10018 (10 + 25 mg / kg) group was smaller than that in the DTX (10 mg / kg) single-drug group, indicating that the combination of DTX and IN10018 had better efficacy than the single-drug groups; the tumor volume in the DTX + IN10018 + MAX10181 (10 + 25 + 120 mg / kg) triple-drug combination group was comparable to that of each single-drug group and each double-drug combination group, but statistically different from that of the other groups, indicating that the combination of DTX, IN10018, and MAX10181 showed better efficacy in inhibiting tumor growth. Administration of MAX10181 to the relevant groups caused diarrhea in the animals and resulted in the death of one animal in each of the MAX10181 (120 mg / kg) and DTX + MAX10181 (10 + 120 mg / kg) groups, but the remaining animals were in good mental and motor condition, indicating that the animals showed some tolerance to the combination of DTX + IN10018 + MAX10181 (10 + 25 + 120 mg / kg).

[0214] Example 10 In Vitro Study on the Induction of Immunogenic Cell Death Targets by Docetaxel and AMP945 in Mouse Breast Cancer 4T1 Cells. Assay materials: 1) Drugs used in this assay Docetaxel was provided by MCE, Lot No.: 111613. AMP945 was provided by MCE, Lot No.: 143253.

[0215] 2) Antibodies used in this assay Recombinant Alexa Fluor® 647 fluorescent anti-calreticulin antibody (Abcam, Cat No.: ab196159, Lot No.: CR33676773). Annexin V-Apoptosis Detection Kit (Beyotime, Cat No.: C1062L, Lot No.: 122221220706).

[0216] Assay Method: 4T1 cells (Nanjing Cobioer Biotechnology Co., Ltd., product number: CBP60352) were cultured in RPMI-1640 (Shanghai Basalmedia, Catalog No.: L210KJ, Lot No.: F210916) + 10% FBS (Gibco, Catalog No.: 10099-141c, Lot No.: 2158737cp) at 37°C and 5% CO2. Trypsin was used for routine digestion and passage twice or three times a week. When the cells were in the exponential growth phase and reached 80%-90% adherent confluence, they were harvested and plated. 4T1 cells were digested with trypsin. The cells were then harvested and counted. According to the counting results, the cells were diluted with RPMI-1640 + 10% FBS, and the dilution concentration was 50,000 cells per ml. Then, the cells were plated into a 12-well culture plate, and 2 ml of cell suspension (100,000 cells) was added to each well. After plating, the cells were cultured in a 37 °C and 5% CO2 incubator. After the cells were seeded for 24 hours, six groups were set up: Group 1 was the control group, and medium was added; Group 2 was AMP945 at a concentration of 3 μM; Group 3 was AMP945 at a concentration of 6 μM; Group 4 was docetaxel at a concentration of 0.3 μM; Group 5 was AMP945 (3 μM) combined with docetaxel (0.3 μM); and Group 6 was AMP945 (6 μM) combined with docetaxel (0.3 μM). The drugs were mixed and the mixture was incubated in a 5% CO2 incubator at 37°C for 48 hours.

[0217] Assay Results After 48 hours of drug action, cells were harvested for flow cytometry. Cells were washed twice with flow buffer (PBS + 2% FBS). 0.5 μl of AF647 anti-calreticulin antibody (Abcam) was added to each well and mixed. Cells were incubated in the dark at 4°C. After 20 minutes of incubation, flow buffer was added. An annexin staining kit (Beyotime) was used. 195 μl of annexin-V-FITC binding solution was added and mixed with the cells by pipetting. 5 μl of annexin-V-FITC antibody was added and mixed gently. Finally, 10 μl of PI dye was added, mixed, and the cells were incubated in the dark at room temperature for 15 minutes. The samples were then sent to a flow cytometer for signal analysis.

[0218] The results of flow cytometry analysis showed that the CRT positive rate and Annexin-V positive rate in the two-drug combination group were significantly better than those in the single-drug group and the control group, as shown in Figures 18a and 18b.

[0219] Example 11 In vitro study of the induction of immunogenic cell death targets by eribulin and AMP945 in mouse breast cancer 4T1 cells. Assay materials: 1) Drugs used in this assay Eribulin was provided by Beijing Chempion Biotechnology Co., Ltd., Lot No.: HG-000000011-000-001. AMP945 was provided by MCE, Lot No.: 143253.

[0220] 2) Antibodies used in this assay Recombinant Alexa Fluor® 647 fluorescent anti-calreticulin antibody (Abcam, Cat No.: ab196159, Lot No.: CR33676773). Annexin V-Apoptosis Detection Kit (Beyotime, Cat No.: C1062L, Lot No.: 122221220706).

[0221] Assay Method: 4T1 cells (Nanjing Cobioer Biotechnology Co., Ltd., product number: CBP60352) were cultured in RPMI 1640 (Shanghai Basalmedia, Catalog No.: L210KJ, Lot No.: F210916) + 10% FBS (Gibco, Catalog No.: 10099-141c, Lot No.: 2158737cp) at 37°C and 5% CO2. Trypsin was used for routine digestion and subculture twice or three times a week. When the cells were in the exponential growth phase and reached 80%-90% adherent confluence, they were harvested and plated. 4T1 cells were digested with trypsin. The cells were then harvested and counted. According to the counting results, the cells were diluted with RPMI-1640 + 10% FBS, and the dilution concentration was 50,000 cells per ml. Then, the cells were plated into a 12-well culture plate, and 2 ml of cell suspension (100,000 cells) was added to each well. After plating, the cells were cultured in a 37 ° C and 5% CO2 incubator. After the cells were seeded for 24 hours, six groups were set up: Group 1 was the control group, and medium was added; Group 2 was AMP945 at a concentration of 3 μM; Group 3 was AMP945 at a concentration of 6 μM; Group 4 was eribulin at a concentration of 0.3 μM; Group 5 was AMP945 (3 μM) combined with eribulin (0.3 μM); and Group 6 was AMP945 (6 μM) combined with eribulin (0.3 μM). The drugs were mixed and the mixture was incubated in a 5% CO2 incubator at 37°C for 48 hours.

[0222] Assay Results After 48 hours of drug action, cells were harvested for flow cytometry. Cells were washed twice with flow buffer (PBS + 2% FBS). 0.5 μl of AF647 anti-calreticulin antibody (Abcam) was added to each well and mixed. Cells were incubated in the dark at 4°C. After 20 minutes of incubation, flow buffer was added. An annexin staining kit (Beyotime) was used. 195 μl of annexin-V-FITC binding solution was added and mixed with the cells by pipetting. 5 μl of annexin-V-FITC antibody was added and mixed gently. Finally, 10 μl of PI dye was added, mixed, and the cells were incubated in the dark at room temperature for 15 minutes. The samples were then sent to a flow cytometer for signal analysis.

[0223] The results of flow cytometry analysis showed that the CRT positive rate and Annexin-V positive rate in the two-drug combination group were significantly better than those in the single-drug group and the control group, as shown in Figures 19a and 19b.

[0224] All references mentioned in this disclosure are incorporated by reference in their entirety as if each document were individually listed. After reading this disclosure, those skilled in the art may make various changes or modifications to the disclosure, and it should be understood that equivalents thereof are also within the scope defined by the claims of this application.

Claims

1. Use of a FAK inhibitor, a microtubule inhibitor, and an immune checkpoint inhibitor in the manufacture of a medicament for treating a tumor in a subject.

2. A pharmaceutical combination of a FAK inhibitor, a microtubule inhibitor and an immune checkpoint inhibitor for use in treating a tumor in a subject.

3. A method for treating a tumor, comprising administering to a subject therapeutically effective amounts of a FAK inhibitor, a microtubule inhibitor, and an immune checkpoint inhibitor.

4. 4. The use, pharmaceutical combination or method according to any one of claims 1 to 3, wherein the FAK inhibitor and the microtubule inhibitor induce immunogenic cell death (ICD).

5. the FAK inhibitor is IN10018, defactinib, GSK2256098, PF-00562271, VS-4718, APG-2449, AMP945, AMP886 or a pharmaceutically acceptable salt thereof; alternatively, the FAK inhibitor is IN10018, defactinib, AMP945 or a pharmaceutically acceptable salt thereof; and further alternatively, the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof; or the FAK inhibitor is IN10018 tartrate, wherein IN10018 is 【Chemical 1】 5. The use, pharmaceutical combination or method according to any one of claims 1 to 4, having the structure:

6. 6. The use, pharmaceutical combination or method according to any one of claims 1 to 5, wherein the microtubule inhibitor is a taxane, eribulin, ixempera or a vinca alkaloid.

7. 7. The use, pharmaceutical combination or method according to any one of claims 1 to 6, wherein the microtubule inhibitor is a taxane.

8. 8. The use, pharmaceutical combination or method according to claim 6 or 7, wherein the taxane is docetaxel, paclitaxel, cabazitaxel or cephalomannine, or is docetaxel or paclitaxel.

9. 9. The use, pharmaceutical combination or method according to any one of claims 1 to 8, wherein the microtubule inhibitor is docetaxel.

10. 9. The use, pharmaceutical combination or method according to any one of claims 1 to 8, wherein the microtubule inhibitor is paclitaxel.

11. 7. The use, pharmaceutical combination or method according to any one of claims 1 to 6, wherein the microtubule inhibitor is eribulin.

12. 12. The use, pharmaceutical combination or method according to any one of claims 1 to 11, wherein the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, a PD-1 / PD-L1 small molecule inhibitor or a TIGIT inhibitor.

13. 13. The use, pharmaceutical combination or method of any one of claims 1 to 12, wherein the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, optionally wherein the anti-PD-1 / PD-L1 antibody is pembrolizumab, tislelizumab, nivolumab, toripalimab, atezolizumab, durvalumab, avelumab, camrelizumab, sintilimab, cemiplimab, embafolimab, BMS-936559, JS003, SHR-1316, GS-4224, AN-4005 or MX-10181.

14. 13. The use, pharmaceutical combination or method of any one of claims 1 to 12, wherein the immune checkpoint inhibitor is a PD-1 / PD-L1 small molecule inhibitor, optionally wherein the PD-1 / PD-L1 small molecule inhibitor is INCB-086550, lazertinib, IMMH-010, CA-170, ABSK043 or RRx-001.

15. 13. The use, pharmaceutical combination or method of any one of claims 1 to 12, wherein the immune checkpoint inhibitor is a TIGIT inhibitor, optionally wherein the TIGIT inhibitor is osipellimab (BGB-A1217), vibostolimab, domvanalimab (AB154), tiragolumab, berlestog, etigilimab, ONO-4686, JS-006, AZD-2936, HLX-301, SEA-TGT, M-6223, IBI-939, COM-902, AB-308, AGEN-1777, AK-127, BAT-6021, BAT-6005, ASP-8374, PM-1022, BMS-986207, HB0036 or IBI-321.

16. 5. The use, pharmaceutical combination or method of any one of claims 1 to 4, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the microtubule inhibitor is docetaxel, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor; or wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the microtubule inhibitor is docetaxel, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody.

17. 5. The use, pharmaceutical combination or method of any one of claims 1 to 4, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the microtubule inhibitor is paclitaxel, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor; or wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the microtubule inhibitor is paclitaxel, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody.

18. 18. The use, pharmaceutical combination or method according to any one of claims 1 to 17, wherein the FAK inhibitor, the microtubule inhibitor and the immune checkpoint inhibitor are administered to the subject simultaneously or sequentially.

19. Metastases caused by tumors including bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer, liver cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma, myeloma, rhabdomyosarcoma, inflammatory myofibroblastoma, neuroblastoma, pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), gastric cancer, testicular cancer, thyroid cancer, uterine cancer, mesothelioma, cholangiocarcinoma, leiomyosarcoma, liposarcoma, nasopharyngeal carcinoma, neuroendocrine carcinoma, ovarian cancer, salivary gland cancer, spindle cell carcinoma, anaplastic large cell lymphoma, 19. The use, pharmaceutical combination or method of any one of claims 1 to 18, wherein the tumor is anaplastic thyroid carcinoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, glioma or a hematological malignancy such as acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL) or chronic myelogenous leukemia (CML); or wherein the tumor is breast cancer, ovarian cancer, colon cancer (including colorectal cancer), lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma or pancreatic cancer.

20. 20. The use, pharmaceutical combination or method according to any one of claims 1 to 19, wherein the tumor is breast cancer, ovarian cancer or colon cancer (including colorectal cancer).

21. (a) FAK inhibitors, (b) microtubule inhibitors and (c) Immune checkpoint inhibitors 20. A kit or pharmaceutically acceptable composition comprising:

22. 22. The kit or composition of claim 21, wherein the FAK inhibitor and the microtubule inhibitor induce immunogenic cell death (ICD).

23. the FAK inhibitor is IN10018, defactinib, GSK2256098, PF-00562271, VS-4718, APG-2449, AMP945, AMP886 or a pharmaceutically acceptable salt thereof; alternatively, the FAK inhibitor is IN10018, defactinib, AMP945 or a pharmaceutically acceptable salt thereof; and further alternatively, the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof; or the FAK inhibitor is IN10018 tartrate, wherein IN10018 is 【Chemistry 2】 23. The kit or composition of claim 21 or 22, having the structure:

24. 24. The kit or composition of any one of claims 21 to 23, wherein the microtubule inhibitor is a taxane, eribulin, ixempera, or a vinca alkaloid.

25. 25. The kit or composition of any one of claims 21 to 24, wherein the microtubule inhibitor is a taxane.

26. 26. The kit or composition of claim 24 or 25, wherein the taxane is docetaxel, paclitaxel, cabazitaxel or cephalomannine, or is docetaxel or paclitaxel.

27. 27. The kit or composition of any one of claims 21 to 26, wherein the microtubule inhibitor is docetaxel.

28. 27. The kit or composition of any one of claims 21 to 26, wherein the microtubule inhibitor is paclitaxel.

29. 25. The kit or composition of any one of claims 21 to 24, wherein the microtubule inhibitor is eribulin.

30. 30. The kit or composition of any one of claims 21 to 29, wherein the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, a PD-1 / PD-L1 small molecule inhibitor, or a TIGIT inhibitor.

31. 31. The kit or composition of any one of claims 21 to 30, wherein the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, optionally wherein the anti-PD-1 / PD-L1 antibody is pembrolizumab, tislelizumab, nivolumab, toripalimab, atezolizumab, durvalumab, avelumab, camrelizumab, sintilimab, cemiplimab, embafolimab, BMS-936559, JS003, SHR-1316, GS-4224, AN-4005, or MX-10181.

32. 31. The kit or composition of any one of claims 21 to 30, wherein the immune checkpoint inhibitor is a PD-1 / PD-L1 small molecule inhibitor, optionally wherein the PD-1 / PD-L1 small molecule inhibitor is INCB-086550, lazertinib, IMMH-010, CA-170, ABSK043, or RRx-001.

33. 31. The kit or composition of any one of claims 21 to 30, wherein the immune checkpoint inhibitor is a TIGIT inhibitor, optionally wherein the TIGIT inhibitor is osipellimab (BGB-A1217), vibostolimab, domvanalimab (AB154), tiragolumab, berlestog, etigilimab, ONO-4686, JS-006, AZD-2936, HLX-301, SEA-TGT, M-6223, IBI-939, COM-902, AB-308, AGEN-1777, AK-127, BAT-6021, BAT-6005, ASP-8374, PM-1022, BMS-986207, HB0036, or IBI-321.

34. 23. The kit or composition of claim 21 or 22, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the microtubule inhibitor is docetaxel, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor; or wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the microtubule inhibitor is docetaxel, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody.

35. 23. The kit or composition of claim 21 or 22, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the microtubule inhibitor is paclitaxel, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor; or wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the microtubule inhibitor is paclitaxel, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody.

36. 36. A kit or composition according to any one of claims 21 to 35, wherein the kit or composition is for use as a medicament.

37. The medicament is used to treat tumors, and the tumors are selected from the group consisting of bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer, liver cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma, myeloma, rhabdomyosarcoma, inflammatory myofibroblastoma, neuroblastoma, pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), stomach cancer, testicular cancer, thyroid cancer, uterine cancer, mesothelioma, cholangiocarcinoma, leiomyosarcoma, liposarcoma, nasopharyngeal cancer, neuroendocrine cancer, ovarian cancer, salivary gland cancer, and spindle cell carcinoma, metastasis, undifferentiated tumors caused by the following:

37. The kit or composition of any one of claims 21 to 36, wherein the tumor is idiopathic large cell lymphoma, anaplastic thyroid carcinoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, glioma, or a hematological malignancy such as acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), or chronic myelogenous leukemia (CML); or wherein the tumor is breast cancer, ovarian cancer, colon cancer (including colorectal cancer), lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma, or pancreatic cancer.

38. 38. The kit or composition of claim 37, wherein the tumor is breast cancer, ovarian cancer, or colon cancer (including colorectal cancer).

39. A FAK inhibitor for use in enhancing immunogenic cell death induced by microtubule inhibitors in the treatment of tumors.

40. the FAK inhibitor is IN10018, defactinib, GSK2256098, PF-00562271, VS-4718, APG-2449, AMP945, AMP886 or a pharmaceutically acceptable salt thereof; alternatively, the FAK inhibitor is IN10018, defactinib, AMP945 or a pharmaceutically acceptable salt thereof; alternatively, the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof; alternatively, the FAK inhibitor is IN10018 tartrate, and IN10018 is 【Chemistry 3】 40. The FAK inhibitor of claim 39, having the structure:

41. 41. The FAK inhibitor of claim 39 or 40, wherein the microtubule inhibitor is a taxane, eribulin, ixempera, or vinca alkaloid.

42. 42. The FAK inhibitor of claim 41, wherein the taxane is docetaxel, paclitaxel, cabazitaxel, or cephalomannine, or is docetaxel or paclitaxel.

43. Metastases caused by tumors including bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer, liver cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma, myeloma, rhabdomyosarcoma, inflammatory myofibroblastoma, neuroblastoma, pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), gastric cancer, testicular cancer, thyroid cancer, uterine cancer, mesothelioma, cholangiocarcinoma, leiomyosarcoma, liposarcoma, nasopharyngeal carcinoma, neuroendocrine carcinoma, ovarian cancer, salivary gland cancer, spindle cell carcinoma, anaplastic large cell lymphoma, anaplastic thyroid carcinoma, non-Hodgkin's lymphoma, thyroid cancer, and ovarian cancer.

43. The FAK inhibitor of claim 39, wherein the tumor is a lymphoma, Hodgkin's lymphoma, glioma, or hematological malignancy, such as acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), or chronic myelogenous leukemia (CML); or wherein the tumor is breast cancer, ovarian cancer, colon cancer (including colorectal cancer), lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma, or pancreatic cancer; further alternatively, wherein the tumor is breast cancer, ovarian cancer, or colon cancer (including colorectal cancer).

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