Pharmaceutical composition containing STING agonist and application thereof
By combining NPC1 inhibitors with STING agonists, the degradation of STING protein was slowed down, and the problem of unsatisfactory efficacy of STING agonists was solved, achieving more efficient anti-tumor effects and lower side effects.
Patent Information
- Application Number
- CN202510105280.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-01-23
- Publication Date
- 2025-03-04
AI Technical Summary
The existing STING agonists are not effective in clinical applications, which may be due to pharmacokinetic instability and inter-patient heterogeneity of STING alleles, and increased side effects caused by rapid degradation of STING proteins upon activation.
The use of NPC1 inhibitors and STING agonists is used to accelerate the anti-tumor effect of STING agonists by slowing down the degradation of STING protein and prolonging its activity time.
It significantly improved the therapeutic effect of STING agonists, reduced the dosage used and reduced side effects, enhanced the activation of cGAS/STING pathway and the expression of type I interferon, and significantly improved the anti-tumor effect.
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Abstract
Description
Technical Field
[0001] The present invention relates to the field of biomedicine technology, and in particular to a pharmaceutical composition containing a STING agonist and an application thereof. Background Art
[0002] The immunomodulatory molecule STING plays a key role in DNA-sensing antiviral immunity. It acts as an endogenous agonist upon detection of aberrant cytosolic DNA and cyclic GMP-AMP (cGAMP), which is synthesized by the key intracellular innate sensor cGAS. Activation of STING can induce the production of proinflammatory cytokines and type I interferons, thereby recruiting adaptive immune cells to eliminate damaged host cells. Therefore, STING plays a central role in both innate and adaptive immunity. In fact, recent studies have demonstrated that intratumoral administration of STING agonists can activate local immunity in the tumor microenvironment (TME), thereby recruiting effector cells to eliminate cancer.
[0003] The development of novel anticancer immunotherapies based on STING has become a hot topic in tumor immunotherapy. Studies have shown that cyclic dinucleotide (CDN) and non-CDN STING agonists have shown promising tumor growth inhibition in mouse syngeneic models and can be used alone or in combination with other immunotherapeutic agents (such as anti-PD-1). Despite significant effects in preclinical studies, limited patient responses have been observed in human clinical trials, which may be due to pharmacokinetic instability or inter-patient heterogeneity of STING alleles. In addition, dysregulation of STING levels in cancer cells is often associated with tumor immune escape, which hinders tumor immune surveillance.
[0004] At present, the existing technologies mainly adopt the following solutions to the problem of unsatisfactory therapeutic effects of STING agonists: (1) developing new STING agonists and improving their binding ability with STING protein through structural optimization; (2) developing new delivery systems to increase the retention time of drugs in tumor sites; (3) using them in combination with other immune checkpoint inhibitors (such as PD-1 antibodies). However, these solutions still have the following limitations, such as the long development cycle of new STING agonists and the need for a large number of clinical trials to verify their safety in humans; the delivery system may bring additional safety issues and increase product costs; and the combination with immune checkpoint inhibitors may lead to an increase in immune-related adverse reactions.
[0005] To overcome these challenges, several CDN and non-CDN STING agonists have been developed that have enhanced pharmacokinetic stability and stronger binding affinity for several alleles of STING. Although various cellular mechanisms of STING selectivity disorders have been elucidated, the available pharmacological approaches are mainly focused on structure-based design and optimization of STING agonists. On the one hand, the human safety of newly developed agonists remains unknown, especially the overactivation of the immune system caused by systemic medication or tumor injection drug spillover poses a huge challenge to the clinical application of STING agonists. On the other hand, after being activated, the STING protein is rapidly degraded by the lysosome, which also leads to the use of STING agonists at a higher dose and a greater chance of side effects.
[0006] Therefore, there is an urgent need to develop a new strategy to improve the therapeutic effect of STING agonists. Studies have found that after being activated, STING protein is rapidly degraded by lysosomes, which is one of the important reasons for the unsatisfactory efficacy of STING agonists. If a method can be found to delay the degradation of STING protein, the therapeutic effect of STING agonists may be significantly improved. Based on these insights, it is hypothesized that slowing the degradation rate of cellular STING in tumor tissues will enhance the immuno-oncology efficacy of STING agonist immunotherapy drugs and achieve the therapeutic effect of STING agonists at low doses.
[0007] Studies have shown that both ligand-dependent and ligand-independent activation of STING require STING translocation from the endoplasmic reticulum (ER) to the ER-Golgi intermediate compartment (ERGIC) and the Golgi apparatus, followed by the recruitment of TANK-binding kinase 1 (TBK1), which activates interferon regulatory factor 3 (IRF3)-interferon (IFN) signaling as well as IFN-independent activities. STING is also recruited to lysosomes for degradation, both at steady state and after activation and trafficking, which inhibits downstream IFN signaling.
[0008] Therefore, it is necessary to develop corresponding compounds in combination with STING agonists to slow down the degradation of STING protein, enhance the immunotherapy effect induced by STING agonists, and improve the therapeutic effect and therapeutic window of STING agonists. Summary of the invention
[0009] Purpose of the invention: The technical problem to be solved by the present invention is to provide a pharmaceutical composition containing a STING agonist and its application in view of the deficiencies of the prior art. The present invention selects an NPC1 inhibitor as a synergistic drug of a STING agonist, evaluates the effect of an NPC1 inhibitor on the STING downstream signaling pathway, and verifies and determines the combination of an NPC1 inhibitor and a STING agonist through multiple tumor models, as well as the anti-tumor effect of the combination.
[0010] In order to solve the above technical problems, the present invention discloses a pharmaceutical composition containing a STING agonist and its application. One purpose of the present invention is to use a Niemann-PickC1 (NPC1) inhibitor in combination with a STING agonist to enhance the anti-tumor effect of the STING agonist. Based on this idea, the present invention proposes an innovative solution to combine an NPC1 inhibitor with a STING agonist to enhance the anti-tumor effect of the STING agonist. The specific technical solution is as follows:
[0011] A pharmaceutical composition comprising a STING agonist and an NPC1 inhibitor.
[0012] Wherein, the STING agonist includes a cyclic dinucleotide STING agonist or a non-cyclic dinucleotide STING agonist; preferably, the STING agonist is a cyclic dinucleotide STING agonist, further preferably 2',3'-cGAMP or 3',3'-cGAMP, and more preferably 2',3'-cGAMP.
[0013] Wherein, the NPC1 inhibitor is selected from any one of itraconazole, posaconazole or U18666A.
[0014] Wherein, the pharmaceutical composition comprises 2',3'-cGAMP and posaconazole.
[0015] Wherein, in the pharmaceutical composition, the mass ratio of the STING agonist to the NPC1 inhibitor is 1:1-20. Preferably, the mass ratio is 1:14.
[0016] Wherein, the pharmaceutical composition promotes the activation of the cGAS / STING pathway and enhances the expression of type I interferon in cells. Preferably, the type I interferon includes IFN-β.
[0017] Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
[0018] Further preferably, the pharmaceutical composition is in the form of a solid preparation, oral liquid or injection. When the pharmaceutical composition of the present invention is prepared into a pharmaceutical preparation, the dosage form of the pharmaceutical preparation is a preparation for injection, oral administration or inhalation administration, including but not limited to: water injection for injection, lyophilized powder for injection, emulsion for injection, suspension for injection, liposome injection, microsphere injection, nanoparticle injection, reservoir-type controlled-release injection, gel-type injection, etc.; in terms of injection devices and packaging, including single-dose / multiple-dose needle-free injections, powder syringes, prefilled injections, powder / liquid premixed syringes, syringes for subcutaneous implantation, etc.; including but not limited to tablets, oral liquids, powders, granules, pills, sustained-release oral dosage forms, etc.; inhalation preparations include but are not limited to sprays, powder mists, atomized therapeutic dosage forms, inhaled dry powders, etc.
[0019] In a second aspect, the present invention provides use of the pharmaceutical composition described in the first aspect in the preparation of anti-tumor drugs.
[0020] Wherein, the tumor is any one of melanoma, colorectal cancer or breast cancer.
[0021] Preferably, in the anti-tumor drug, the STING agonist and the NPC1 inhibitor are combined, and the STING agonist and the NPC1 inhibitor can be administered simultaneously or separately; wherein, the STING agonist is administered by injection or oral administration, and the NPC1 inhibitor is administered by injection or oral administration. Preferably, the STING agonist and the NPC1 inhibitor are administered separately; wherein, the STING agonist is administered by injection, and the NPC1 inhibitor is administered orally.
[0022] Beneficial effects: The pharmaceutical composition of the present invention has simple components, high safety, and is easy to use. It has strong feasibility for clinical implementation and has strong social significance and economic benefits. The beneficial effects of the present invention are as follows: The present invention discovered and confirmed that NPC1 inhibitors can enhance the activation of the cGAS / STING pathway by STING agonists, thereby enhancing the expression of type I interferons (such as IFN-β) in cells, thereby exerting a better anti-tumor effect.
[0023] The present invention significantly improves the therapeutic effect of STING agonists, and shows enhanced anti-tumor effects in multiple tumor models (B16F10 melanoma, MC38 colon cancer, 4T1 breast tumor); NPC1 inhibitors can reduce the dosage of STING agonists and reduce side effects by promoting the activation of the cGAS / STING pathway by STING agonists. In general, the present invention provides a new strategy to enhance the activation of the STING pathway, providing new ideas for tumor immunotherapy. BRIEF DESCRIPTION OF THE DRAWINGS
[0024] The present invention will be further described in detail below in conjunction with the accompanying drawings and specific embodiments, and the above and / or other advantages of the present invention will become more clear.
[0025] Figure 1 Figure 2 is the IFN-β level after synergistic action of NPC1 inhibitor and STING agonist in RAW264.7 cells.
[0026] Figure 2 Figure 2 is the IFN-β level after synergistic action of NPC1 inhibitor and STING agonist in BMDC cells.
[0027] Figure 3 Figure 2 is the IFN-β level after NPC1 inhibitor and STING agonist synergistically acted in THP1 cells or RAW264.7 cells.
[0028] Figure 4 The combination of NPC1 inhibitor and STING agonist has a synergistic effect on dendritic cell activation.
[0029] Figure 5 The effect of the drug combination of NPC1 inhibitor and STING agonist on the expression of interferon gene stimulator in the STING downstream pathway.
[0030] Figure 6 The antitumor effect of a drug combination of NPC1 inhibitor and STING agonist on B16F10 melanoma.
[0031] Figure 7 The antitumor effect of a drug combination of NPC1 inhibitor and STING agonist on MC38 colorectal cancer.
[0032] Figure 8 The antitumor effect of a drug combination of an NPC1 inhibitor and a STING agonist on 4T1 breast cancer tumors. DETAILED DESCRIPTION
[0033] The present invention is further illustrated below through the description of specific implementation modes, but this is not a limitation of the present invention. Those skilled in the art can make various modifications or improvements based on the basic idea of the present invention, but as long as they do not deviate from the basic idea of the present invention, they are all within the scope of the present invention.
[0034] The cGAMP described in the following examples is all 2',3'-cGAMP.
[0035] In the following examples, the posaconazole and STING agonist 2', 3'-cGAMP were purchased from McLean; the U18666A and itraconazole were purchased from MCE; the IFN-β detection kit was purchased from Link Bio; the LPS was purchased from Bio-Time; the CD11c, CD40, CD80 and CD86 flow cytometry antibodies were purchased from Biolegend; the RNA extraction kit was purchased from Quanshijin; the reverse transcription kit and qPCR fluorescence quantification kit were purchased from Novazonics.
[0036] In the following examples, the PBS used, unless otherwise specified, has an ion concentration of 0.01 M and a pH of 7.4-7.6.
[0037] Example 1 Synergistic effect of the combination of NPC1 inhibitor and STING agonist in RAW264.7 cells This example investigates the enhancing effect of various NPC1 inhibitors on STING agonists and studies the ability of three different NPC1 inhibitors (posaconazole, itraconazole, and U18666A) to synergistically produce IFN-β with the STING agonist cGAMP in the RAW264.7 cell line.
[0038] RAW264.7 cells were routinely digested and plated in 96-well cell culture plates, and the experiment was started when the cells were about 70% confluent. The groups were as follows: Synergistic group: different NPC1 inhibitors (posaconazole, itraconazole or U18666A) and STING agonist cGAMP were added to the cells for synergistic effect, and cGAMP+posaconazole group, cGAMP+itraconazole group or cGAMP+U18666A group were obtained respectively; NPC1 inhibitor group: NPC1 inhibitor (posaconazole, itraconazole, or U18666A) was added to the cells alone; STING agonist group: STING agonist cGAMP was added to the cells alone; Blank group: no drug added; The dosage of cGAMP added was 5 μg / mL, the dosage of NPC1 inhibitor added was a safe concentration dosage, the dosage of posaconazole added was 5 μM, the dosage of itraconazole added was 1.25 μM, and the dosage of U18666A added was 0.78125 μM. After the above drugs were co-cultured with cells at 37 °C for 24 h, the cell supernatant was collected, and the IFN-β content in the supernatant was detected using an IFN-β detection kit.
[0039] The results are as follows Figure 1As shown in the figure, different NPC1 inhibitors (itraconazole, posaconazole and U18666A) can cooperate with the STING agonist cGAMP to activate the STING pathway in RAW264.7 cells, produce higher IFN-β levels, and enhance the effect of the STING agonist. Compared with the blank group and the NPC1 inhibitor group, the IFN-β production level of the STING agonist group was significantly increased, and the synergistic group of the combination of the two compounds of the NPC1 inhibitor and the STING agonist achieved a higher IFN-β level than the STING agonist group, among which posaconazole and itraconazole had the most significant effect. The insignificant effect of the synergistic group of some NPC1 inhibitors such as U18666A and cGAMP may be due to poor solubility and absorption. It is speculated that better effects can be obtained by changing their pharmacokinetic properties. Therefore, the above studies have proved that NPC1 inhibitors can cooperate with the STING agonist cGAMP to activate the STING pathway and produce higher IFN-β levels.
[0040] Example 2 Synergistic effects of the combination of NPC1 inhibitors and STING agonists in different cell lines This example mainly investigates the enhancing effect of NPC1 inhibitors on STING agonists on different cells, and observes the activation effect of STING pathway after the combination of STING agonists and NPC1 inhibitors on cells in THP-1, RAW264.7 and bone marrow-derived dendritic cell (BMDC) cell lines. This example studies the ability of NPC1 inhibitors represented by posaconazole and STING agonists represented by cGAMP to activate the STING pathway in different cell lines.
[0041] The culture methods of different cells are as follows: RAW264.7, THP1 and BMDC cells were plated into 96-well cell culture plates. For the cell lines RAW264.7 and THP1, the drug addition test was started when the cells were confluent to about 70%. For the primary cell line BMDC, 6-week-old BALB / c mice were taken, killed by cervical dislocation, and placed in 75% alcohol for 5 min for disinfection. The skin of the abdomen and legs was cut with scissors, the tibia and femur were taken, and the bones were rinsed with PBS with a syringe, centrifuged at 2000 rpm for 8 min, 2-3mL of red blood cell lysis buffer was added, and the mixture was mixed and lysed for 2 min. The culture medium with 2 times the volume of red blood cell lysis buffer was added to terminate the lysis, centrifuged at 2000rpm for 8 min, the supernatant was discarded, and the complete culture medium was added to mix, the cells were counted, and the cell density was adjusted to 10 using complete dendritic cell culture medium (10% fetal bovine serum + 40 ng / mL IL4 + 40 ng / mL colony stimulating factor). 6 / mL. Half of the medium was replaced with complete dendritic cell culture medium every two days, and the cells were treated with drugs on the seventh day to start the experiment.
[0042] The groups are as follows: Synergistic group: different concentrations of NPC1 inhibitor posaconazole and STING agonist cGAMP were added to the cells for synergistic effect; NPC1 inhibitor group: different concentrations of NPC1 inhibitor posaconazole were added to the cells alone; STING agonist group: STING agonist cGAMP was added to the cells alone; Blank group: no drug added; The added dose of cGAMP was 10 μg / mL, and the added doses of different concentrations of posaconazole were 0, 5 μM, and 10 μM. After the drugs and cells were co-cultured at 37 °C for 24 h, the cell supernatants were collected, and the IFN-β detection kit was used to detect the content of IFN-β in the supernatants of RAW264.7, BMDC, and THP1 cells.
[0043] The results showed that NPC1 inhibitors can cooperate with STING agonist cGAMP to activate the STING pathway in different cell lines, produce higher IFN-β levels, and enhance the effect of STING agonists. Figure 2 and Figure 3 As shown, in each of the above cell lines, the IFN-β production level of the STING agonist group was significantly increased compared with the blank group and the NPC1 inhibitor group, while the synergistic group of the two compounds achieved a higher IFN-β level than the STING agonist group. Therefore, the above studies prove that the synergistic effect of NPC1 inhibitors on the activation of the STING pathway by the STING agonist cGAMP is a general phenomenon that is independent of the type of cell line.
[0044] Example 3 Combination of NPC1 inhibitor and STING agonist promotes DC cell activation This example mainly investigates the effect of NPC1 inhibitor on STING agonist-promoted DC cell activation. It was observed in BMDC cells that the combination of NPC1 inhibitor and STING agonist promoted DC cell activation.
[0045] According to the method in Example 2, mouse bone marrow-derived dendritic cells (BMDCs) were plated in 24-well cell culture plates and grouped as follows: Synergistic group: cGAMP and NPC1 inhibitor posaconazole were added to the cells; NPC1 inhibitor group: NPC1 inhibitor posaconazole was added to the cells alone; STING agonist group: STING agonist cGAMP was added to the cells alone; Blank group: no drug added; Positive control group: LPS was added to the cells; The dosage of cGAMP was 10 μg / mL; the dosage of posaconazole was 10 μM; and the dosage of LPS was 1 μg / mL. After the drug and cells were co-cultured for 24 h or 48 h, the cells were collected, centrifuged at 4000 rpm for 5 min, and washed twice with PBS. Fluorescent labeled antibodies were added and incubated for 30 min in the dark to label the cells. After incubation, the cells were centrifuged and washed twice with PBS, and the expression of cell surface marker molecules CD11c, CD40, and CD86 was detected by flow cytometry.
[0046] The results are as follows Figure 4 As shown, NPC1 inhibitors can significantly promote the effect of STING agonists on DC activation. Compared with the use of cGAMP alone, the synergistic group of posaconazole and cGAMP significantly increased the ratio of dendritic cell surface molecular markers CD40 and CD86, promoting DC activation.
[0047] Example 4 Combination of NPC1 inhibitor and STING agonist enhances the expression of interferon-stimulated factors in the STING downstream pathway In this example, the enhancing effect of the combination of NPC1 inhibitor and STING agonist on the expression of interferon-stimulated factor in the STING downstream pathway was observed in THP1 cells.
[0048] THP1 cells were plated in a 12-well cell culture plate. After the cells were confluent to 70%, a synergistic group of cGAMP and NPC1 inhibitor posaconazole was added to the cells. At the same time, an NPC1 inhibitor group in which NPC1 inhibitor was added to the cells alone, a STING agonist group in which STING agonist was added to the cells alone, and a blank group without any drug were set up. The added dose of cGAMP was 10 μg / mL; the added dose of posaconazole was 10 μM. After the drugs were co-cultured with the cells for 6-9 h, the cells were collected, RNA was extracted using an RNA extraction kit, and reverse transcribed into cDNA using a reverse transcription kit. The mRNA expression levels of interferon-stimulated factors interferon-β (IFN-β), CXC chemokine ligand 10 (CXCL-10), interferon-stimulated gene 15 (ISG-15), 2',5' oligoadenylate synthetase 3 (Oas3), interferon-induced protein with tetratricopeptide repeats 1 (IFIT1), interferon α-induced protein 27 (IFI27), interferon regulatory factor 7 (IRF7), chemokine 2 (CCL2), and CXC chemokine ligand 9 (CXCL-9) were detected using a qPCR fluorescence quantitative kit.
[0049] The results are as follows Figure 5 As shown, NPC1 inhibitors can significantly promote the STING downstream pathway activated by STING agonists, and the relative expression level of interferon-stimulated factor mRNA is significantly increased.
[0050] Example 5 Effects of a combination of STING agonists and NPC1 inhibitors on B16 melanoma in mice In this example, the anti-tumor efficacy of the combination of a STING agonist and an NPC1 inhibitor was studied in a syngeneic tumor model (B16 melanoma) in mice.
[0051] To evaluate the therapeutic activity of the combination of STING agonists and NPC1 inhibitors, C57BL / 6 immune competent mice (5-6 weeks old, 15-17 g) were implanted subcutaneously in the right flank with B16F10 melanoma cells at 10 6 After 9 days, when the tumor volume was 50-100 mm 3 The mice were administered drugs between: cGAMP group: 10 μg of STING agonist cGAMP was administered alone; Posaconazole group: 140 μg of NPC1 inhibitor posaconazole alone was administered; cGAMP+psaconazole group: The two drugs were administered in combination, and 10 μg of STING agonist was injected intratumorally immediately after oral gavage of 140 μg of NPC1 inhibitor posaconazole; Blank group: no drug was administered.
[0052] The administration was repeated every 3 days, and a total of 3 doses were administered for 9 days. The STING agonist cGAMP was administered by intratumoral injection after being configured as an injection using lipo liposomes (liposome transfection reagent, purchased from Yisheng Biotechnology Co., Ltd.), and the NPC1 inhibitor posaconazole was administered orally. The changes in tumor volume and survival of the mice after administration were observed and recorded.
[0053] The results are as follows Figure 6 As shown, compared with the blank group, the combination of NPC1 inhibitor and STING agonist can significantly reduce the growth rate of mouse tumor volume and increase the survival time of mice.
[0054] Example 6 Effect of STING agonist and NPC1 inhibitor combination on MC38 colorectal cancer tumors in mice In this example, the anti-tumor efficacy of the combination of a STING agonist and an NPC1 inhibitor was studied in a syngeneic tumor model (MC38 colorectal cancer tumor) in mice.
[0055] To evaluate the therapeutic activity of the combination of STING agonists and NPC1 inhibitors, C57BL / 6 mice (5-6 weeks old, 15-17 g) were implanted subcutaneously in the right flank with MC38 tumor cells at 10 6 After 9 days, when the tumor volume was 50-100mm 3 Between 1 and 2 weeks, 10 μg of STING agonist cGAMP was administered alone into the mouse tumor, 140 μg of NPC1 inhibitor posaconazole was orally administered, or both drugs were administered in combination. The administration was repeated every 3 days for a total of 3 doses, and the administration method and grouping were the same as in Example 5. After administration, the changes in tumor volume and survival of the mice were observed and recorded.
[0056] The results are as follows Figure 7 As shown, compared with the other control groups, the combination of NPC1 inhibitor and STING agonist can significantly reduce the growth rate of mouse tumor volume and increase the survival time of mice.
[0057] Example 7 Effects of a combination of STING agonists and NPC1 inhibitors on breast cancer tumors in mice In this example, the anti-tumor efficacy of the combination of a STING agonist and an NPC1 inhibitor was studied in a syngeneic tumor model (4T1 breast cancer tumor) in mice.
[0058] To evaluate the therapeutic activity of the combination of STING agonists and NPC1 inhibitors, BALB / c mice (5-6 weeks old, 15-17 g) were implanted subcutaneously in the right flank with 4T1 tumor cells at 10 6 After 9 days, when the tumor volume was 50-100mm 3 Between 1 and 2 weeks, 10 μg of STING agonist cGAMP was administered alone into the mouse tumor, 140 μg of NPC1 inhibitor posaconazole was orally administered, or both drugs were administered in combination. The administration was repeated every 3 days for a total of 3 doses, and the administration method and grouping were the same as in Example 5. After administration, the changes in tumor volume and survival of the mice were observed and recorded.
[0059] The results are as follows Figure 8 As shown, compared with the other control groups, the combination of NPC1 inhibitor and STING agonist can significantly reduce the growth rate of mouse tumor volume and increase the survival time of mice.
[0060] The present invention provides a pharmaceutical composition containing a STING agonist and a method and idea for its application. There are many methods and approaches to implement the technical solution. The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention. All components not specified in this embodiment can be implemented by existing technologies.
Claims
1. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises a STING agonist and an NPC1 inhibitor.
2. The pharmaceutical composition according to claim 1, characterized in that The STING agonist is a cyclic dinucleotide STING agonist or a non-cyclic dinucleotide STING agonist.
3. The pharmaceutical composition according to claim 2, characterized in that The STING agonist is a cyclic dinucleotide STING agonist.
4. The pharmaceutical composition according to claim 3, characterized in that The cyclic dinucleotide STING agonist is 2',3'-cGAMP or 3',3'-cGAMP.
5. The pharmaceutical composition according to claim 1, characterized in that The NPC1 inhibitor is selected from any one of itraconazole, posaconazole or U18666A.
6. The pharmaceutical composition according to claim 1, characterized in that The pharmaceutical composition comprises 2',3'-cGAMP and posaconazole.
7. The pharmaceutical composition according to claim 1, characterized in that In the pharmaceutical composition, the mass ratio of the STING agonist to the NPC1 inhibitor is 1:1-20.
8. The pharmaceutical composition according to claim 1, characterized in that The pharmaceutical composition promotes the activation of the cGAS / STING pathway and enhances the expression of type I interferon in cells.
9. Use of the pharmaceutical composition according to any one of claims 1 to 8 in the preparation of anti-tumor drugs.
10. The use according to claim 9, characterized in that: The tumor is any one of melanoma, colorectal cancer or breast cancer.