Application of SMURF1 inhibitor, synergistic immune composition and application of synergistic immune composition
By synergistically applying SMURF1 inhibitors and PD-1/PD-L1 inhibitors, the tumor microenvironment was regulated, the problem of insufficient CD8+ T cell infiltration was solved, and the immunotherapy effect of lung adenocarcinoma was significantly improved.
Patent Information
- Application Number
- CN202511754114.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Priority Date
- 2025-11-24
- Filing Date
- 2025-11-26
- Publication Date
- 2026-01-23
AI Technical Summary
Current immunotherapy has drawbacks such as insufficient CD8+ T cell infiltration, low response rate to PD-1/PD-L1 inhibitors, and easy development of drug resistance, especially in non-small cell lung cancer where the clinical response rate is insufficient.
A synergistic immune composition consisting of an SMURF1 inhibitor and PD-1 and/or its ligand PD-L1 inhibitor was used to regulate the tumor immune microenvironment. By upregulating STAT1 protein and its phosphorylation level, it promoted the expression of CXCL9 and CXCL10 chemokines, enhanced CD8+ T cell infiltration, and improved the tumor immune microenvironment.
It significantly increases the infiltration density of CD8+ T cells in tumor tissue, enhances the immune response, solves the problem of insufficient response rate of PD-1 inhibitors in lung adenocarcinoma, and achieves a stronger tumor suppression effect.
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Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to the field of biological medicine, more particularly, to the application of SMURF1 inhibitor and synergistic immune composition and the application thereof. BACKGROUND
[0002] Lung cancer is the leading cause of cancer-related deaths worldwide, of which non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancer cases, and lung adenocarcinoma (LUAD) is the most common subtype. Despite the continuous progress of molecular targeted therapy and immunotherapy, the overall five-year survival rate of patients with advanced NSCLC is still not ideal.
[0003] In recent years, immune checkpoint inhibitors (ICB) represent a new direction for tumor treatment. Drugs represented by inhibitors of programmed death 1 (PD-1) and its ligand (PD-L1) significantly improve the clinical prognosis of some patients by relieving immune suppression in the tumor microenvironment, restoring CD8 + T cell cytotoxic activity. However, a large number of clinical studies have shown that the objective response rate of ICB monotherapy is usually less than 30%, and about 80% of patients are difficult to obtain a sustained immune response, and often develop resistance within 4 to 10 months after initial response.
[0004] One of the main reasons for drug resistance is the insufficient infiltration and activation of effector T cells in the tumor microenvironment (TME). Tumor tissues can be divided into "hot tumors" and "cold tumors" according to the immune status. "Hot tumors" contain a large number of activated CD8+ T cells and antigen-presenting cells, and are easy to respond to immunotherapy; while in "cold tumors", CD8+ T cells are blocked at the edge of the tumor or are rare, forming an "immune rejection" or "immune desert" subtype, resulting in ineffective immunotherapy.
[0005] Existing technologies have attempted to improve this problem through various ways, such as: exogenous supplement of chemokines or activation of their receptors to enhance the directional migration of T cells; using anti-angiogenic drugs to promote vascular normalization to facilitate the extravasation of immune cells; modulating the stromal barrier by inhibiting TGF-β or targeting cancer-associated fibroblasts; restoring T cell function by combining with cytokines or other immune agonists, etc.
[0006] These strategies can improve T cell infiltration to some extent, but there are still problems such as non-specific drug targets, large side effects, complex combination therapy, and poor clinical reproducibility. SUMMARY
[0007] The present application is to overcome the defects of insufficient CD8 + T cell infiltration, low response rate of PD-1 / PD-L1 inhibitors and drug resistance, and provides an application of a SMURF1 inhibitor; Another object of the present application is to provide a synergistic immune composition. Another object of the present application is to provide an application of a synergistic immune composition.
[0008] To solve the above technical problems, the technical solutions of the present application are as follows: An application of a SMURF1 inhibitor for preparing a drug for regulating CD8 + T cell infiltration in tumor immune microenvironment.
[0009] Preferably, the SMURF1 inhibitor comprises [4-[[4-chloro-3-(trifluoromethyl)phenyl] sulfonyl]-1-piperazinyl][4-(5-methyl-1H-pyrazol-1-yl)phenyl]methanone (code: A01).
[0010] Further, for preparing a drug for regulating STAT1 protein level and expression of CXCL9 and CXCL10 chemokines.
[0011] Further, for preparing a drug for enhancing the anti-tumor immune response of PD-1 and / or its ligand PD-L1 inhibitors.
[0012] Further, for preparing an immunotherapy drug for tumors related to up-regulation of SMURF1 expression or abnormal activity.
[0013] A synergistic immune composition comprises a SMURF1 inhibitor, a PD-1 and / or its ligand PD-L1 inhibitor.
[0014] Further, the mass ratio of the SMURF1 inhibitor to the PD-1 and / or its ligand PD-L1 inhibitor is 1:10-2000.
[0015] An application of the synergistic immune composition for preparing a drug for regulating CD8
[0016] Further, for preparing a drug for regulating STAT1 protein level and expression of CXCL9 and CXCL10 chemokines.
[0017] Furthermore, it is used to prepare drugs that inhibit tumor growth.
[0018] Furthermore, the tumors were associated with upregulated SMURF1 expression or abnormal activity.
[0019] Compared with the prior art, the beneficial effects of the technical solution of the present invention are: The SMURF1 inhibitor and its synergistic immunomodulatory composition with PD-1 and / or PD-L1 inhibitors provided by this invention exhibit significant tumor-suppressive and immunomodulatory effects. Treatment with SMURF1 inhibitors or in combination with PD-1 and / or PD-L1 inhibitors upregulates STAT1 protein and its phosphorylation levels, promotes the expression and secretion of T cell chemokines such as CXCL9 and CXCL10, thereby enhancing CD8+ expression. + T cell infiltration density in tumor tissue and significantly increased GZMB + CD8 + T and IFN-γ + CD8 + This invention improves the tumor immune microenvironment by increasing the proportion of T cells. It is applicable to tumor types associated with upregulated SMURF1 expression or abnormal activity, organically combining the two pathways of "promoting T cell recruitment" and "relieving T cell suppression," thus solving the clinical challenge of insufficient response rates of current PD-1 inhibitors in LUAD. Attached Figure Description
[0020] Figure 1 Immunohistochemical images of SMURF1 in LUAD cancer (A) and adjacent normal tissue (B).
[0021] Figure 2 The effect of SMURF1 on mouse body weight. (A) Schematic diagram of subcutaneous xenograft model, (B) Body weight growth rate curves of the shctrl and shSMURF1 groups (n=6; ns: P >0.05).
[0022] Figure 3 The growth of Lewis cell subcutaneous xenografts in C57BL / 6 mice. (A) Curves showing the change in subcutaneous xenograft volume over time in the shctrl and shSMURF1 groups; (B) Representative photographs (left) and qualitative analysis of tumor weight (right) in the shctrl and shSMURF1 groups (n=6; **** P <0.0001).
[0023] Figure 4 CD8 in TME + T cell infiltration. (A) Immunofluorescence comparison of tumor tissues from the shctrl and shSMURF1 groups, (B) CD8 +Quantitative statistical analysis of T cell infiltration density (n=7~8; ****) P <0.0001).
[0024] Figure 5 CD8 in TME + T cell infiltration status. (A) CD8 in tumor tissues of shctrl and shSMURF1 groups. + Representative image of T cell detection, (B) CD8 + Quantitative statistical analysis of T cell infiltration density ( n =4;*** P <0.001).
[0025] Figure 6 GZMB in TME + CD8 + T cell infiltration status. (A) GZMB tumor tissue from the shctrl and shSMURF1 groups. + CD8 + Representative image of T cell detection, (B) GZMB + CD8 + Quantitative statistical analysis of T cell infiltration density ( n =6;*** P <0.001).
[0026] Figure 7 For IFN-γ in TME + CD8 + T cell infiltration status. (A) IFN-γ in tumor tissues of shctrl and shSMURF1 groups. + CD8 + Representative image of T cell detection, (B) IFN-γ + CD8 + Quantitative statistical analysis of T cell infiltration density ( n =4;** P <0.01).
[0027] Figure 8 A schematic diagram of A01 application model in C57BL / 6 mice. (A) Schematic diagram of subcutaneous xenograft model, (B) Weight gain rate curves of the shctrl and shSMURF1 groups. n =6; ns: P >0.05).
[0028] Figure 9 The effect of A01 on the growth of Lewis cell subcutaneous xenografts in C57BL / 6 mice. (A) Curves showing the change in subcutaneous xenograft volume over time in the DMSO and A01 groups. n=6), (B) Representative photographs (left) and quantitative analysis of tumor weight (right) of DMSO and A01 groups (Diagrams). n =6;*** P <0.001, **** P <0.0001).
[0029] Figure 10 Promote CD8 for A01 + T-mediated infiltration into the TME. (A) CD8 in tumor tissues of DMSO and A01 groups. + Representative image of T cell detection, (B) CD8 + Quantitative statistical analysis of T cell infiltration density (n=6; ***) P <0.001).
[0030] Figure 11 Promote GZMB for A01 + CD8 + T-mediated infiltration into TME. (A) GZMB in tumor tissues from DMSO and A01 groups. + CD8 + Representative image of T cell detection, (B) GZMB + CD8 + Quantitative statistical analysis of T cell infiltration density (n=5; *) P <0.05).
[0031] Figure 12 A01 promotes IFN-γ + CD8 + T-mediated infiltration into the TME. (A) IFN-γ in tumor tissues of DMSO and A01 groups. + CD8 + Representative image of T cell detection, (B) IFN-γ + CD8 + Quantitative statistical analysis of T cell infiltration density (n=6; *) P <0.05).
[0032] Figure 13 The expression of STAT1 and CXCL9 / CXCL10 proteins in C57BL / 6 mice. (A) Western blot results of STAT1, CXCL9 and CXCL10 protein expression in tumor tissues of C57BL / 6 mice in DMSO and A01 groups. (B) Quantitative statistical analysis of the gray values of the target protein bands in Figure A. n =3;*** P<0.001), (C) Western blot results of SMURF1, STAT1, pSTAT1, CXCL9 and CXCL10 proteins in tumor tissues of the shctrl, shSMURF1 and shSMURF1+Fludarabine treatment groups; (D) Quantitative statistical analysis of the gray values of the target protein bands in Figure C (n=3; **** P <0.0001).
[0033] Figure 14 To knock down the anti-tumor effect of SMURF1 and CD8 + The relationship between T cells. (A) CD8 + (A) Schematic diagram of T cell exhaustion experiment design; (B) Tumor growth curves of each group; (C) Representative tumor photographs at the endpoint; (D) Statistical results of tumor weight. n =5; ns: P >0.05, * P <0.05,** P <0.01, *** P <0.001, **** P <0.0001).
[0034] Figure 15 This is to illustrate the anti-tumor effect of A01 combined with a PD-1 inhibitor. (A) Schematic diagram of A01 combined with PD-1 treatment model, (B) Tumor volume statistics curves for each group, (C) Representative tumor graphs for each group, (D) Tumor weight statistics. n =5;** P <0.01, **** P <0.0001).
[0035] Figure 16 For A01 combined with PD-1 inhibitors to target CD8 in tumor tissue + Effects of T cell infiltration. (A) CD8 in tumor tissues of the IgG control group, PD-1 monotherapy group, A01 monotherapy group, and A01+PD-1 combination group. + Representative T cell flow cytometry findings; (B) CD8 in each group + Quantitative statistical analysis of the infiltration ratio of T cells in tumor tissue (n=5; ****) P <0.0001).
[0036] Figure 17 For A01 combined with PD-1 inhibitors to target GZMB in tumor tissue + CD8 + Effects on T cells. (A) GZMB in tumor tissues of the IgG control group, PD-1 monotherapy group, A01 monotherapy group, and A01+PD-1 combination group. + CD8+ Representative diagram of T cell detection; (B) GZMB in each group + CD8 + Quantitative statistical analysis of T cell proportion (n=5; *) P <0.05,** P <0.01).
[0037] Figure 18 The effect of A01 combined with PD-1 inhibitors on IFN-γ in tumor tissue + CD8 + Effects on T cells. (A) IFN-γ in tumor tissues of the IgG control group, PD-1 monotherapy group, A01 monotherapy group, and A01+PD-1 combination group. + CD8 + Representative diagram of T cell detection; (B) IFN-γ in each group + CD8 + Quantitative statistical analysis of T cell proportion (n=5; **) P <0.01, *** P <0.001). Detailed Implementation
[0038] The present invention will be further described below with reference to the accompanying drawings and specific embodiments, but the embodiments do not limit the present invention in any way. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in this technical field.
[0039] Unless otherwise specified, all reagents and materials used in the following examples are commercially available.
[0040] SMURF1 inhibitors include [4-[[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl]-1-piperazinyl][4-(5-methyl-1H-pyrazol-1-yl)phenyl] ketone (code name: A01).
[0041] Example 1 Application of SMURF1 in regulating the tumor immune microenvironment (1) Bioinformatics analysis of SMURF1 expression in lung adenocarcinoma, immunohistochemical verification of SMURF1 expression in clinical lung adenocarcinoma specimens, and detection of high SMURF1 expression in human adenocarcinoma lung adenocarcinoma cell lines.
[0042] (2) A subcutaneous xenograft model was established in immunocompetent C57BL / 6 mice using the constructed Lewis-shSMURF1 cell line. Figure 2 A). The mouse body weight gain rate, tumor volume, and weight changes were systematically monitored. At the end of the observation period, flow cytometry or immunofluorescence was used to detect CD8+ in the tumor tissue. + T cell percentage, GZMB+ CD8 + T cell percentage and IFN-γ + CD8 + T cell ratio.
[0043] (3) A subcutaneous xenograft model was established in C57BL / 6 mice with intact immune systems using Lewis lung cancer cells. Figure 8 A). The experiment included a control group (DMSO solvent) and an A01 treatment group. A01 was administered via intraperitoneal injection at a dose of 0.15 mg / kg, once every 3 days. Changes in mouse body weight, dynamic growth of tumor volume, and differences in final tumor weight were systematically monitored. At the end of the observation period, CD8+ in tumor tissue was detected by flow cytometry or immunofluorescence. + T cell percentage, GZMB + CD8 + T cell percentage and IFN-γ + CD8 + T cell ratio.
[0044] Example 2 Application of SMURF1 inhibition in enhancing immune cell function and regulating the expression of related molecules (1) The changes of downstream molecules STAT1, CXCL9 and CXCL10 at the gene and protein levels were detected by qRT-PCR and Western Blot, and the effect of SMURF1 on their expression was analyzed. (2) A C57BL / 6 mouse subcutaneous xenograft model was constructed using mouse Lewis lung cancer cells, and anti-CD8 was applied. + T-cell antibodies target CD8 + T cell exhaustion assay Figure 14 A). 1×10 6 Lewis tumor cells treated with shctrl or shSMURF1 were subcutaneously inoculated into the right axilla of mice. Starting from day 7 after inoculation, anti-CD8 antibody (200 μg / mouse) was administered intraperitoneally every 3 days to achieve CD8 antibody control. + T cell depletion was observed; the control group received an equal amount of IgG isotype control antibody. Tumor volume changes were continuously monitored throughout the experiment. At the endpoint, tumor samples were harvested for flow cytometry or immunoassay to investigate whether the knockdown of SMURF1-mediated antitumor effect depends on CD8+ in the tumor microenvironment. + T cells.
[0045] Example 3 Application of synergistic immunomodulatory compositions and combined therapy for tumors In vivo experiments were conducted to investigate the synergistic antitumor effect of the combined use of the SMURF1 inhibitor A01 and the PD-1 inhibitor.Figure 15 A). In a Lewis lung cancer subcutaneous xenograft model in C57BL / 6 mice, four groups were established: IgG ctrl, anti-PD-1, A01, and A01+anti-PD-1. Starting from day 7 after inoculation, A01 (0.15 mg / kg, every 3 days) or an equivalent volume of DMSO was administered intraperitoneally, along with concurrent injections of PD-1 antibody (200 μg / mouse, every 3 days) or IgG control (…). Figure 13 A). Systematically monitor changes in mouse body weight gain rate, tumor volume, and weight. Detect CD8+ in tumor tissue using flow cytometry or immunofluorescence. + T cell percentage, GZMB + CD8 + T cell percentage and IFN-γ + CD8 + T cell ratio.
[0046] Analysis and Explanation Figure 1 SMURF1 is highly expressed in lung adenocarcinoma, but its expression is low in adjacent normal tissues, indicating that SMURF1 is specifically associated with lung adenocarcinoma tumor tissue.
[0047] (a) Results of SMURF1 knockdown experiment After knocking down the SMURF1 gene in Lewis lung cancer cells, the treated and control cells were subcutaneously inoculated into C57BL / 6 mice to establish xenograft models. Results showed that tumor growth was significantly slowed in the SMURF1 knockdown group, and the tumor weight at the final harvest was significantly lower than that in the control group. Figure 3 The trend of mouse body weight change over time was consistent, and there was no statistically significant difference between groups. Figure 2 This indicates that SMURF1-targeted intervention can inhibit tumor growth without affecting the body's normal metabolic state, demonstrating good biosafety and specificity.
[0048] Immunofluorescence assays were performed on tumor tissue, and the results showed that CD8+ knockdown was observed in the SMURF1 group. + T cell positive signal significantly increased ( Figure 4 In a Lewis lung cancer C57BL / 6 mouse xenograft model, single-cell suspensions of tumor tissues from the shctrl and shSMURF1 groups were analyzed by flow cytometry. Results showed that CD8+ was present in tumor tissues from the shSMURF1 group. + The proportion of T cells was significantly higher than that in the control group. Figure 5 After knocking down SMURF1, CD8 + T cell infiltration within tumor tissue was significantly increased. Further detection of CD8... +T cell cytotoxicity markers showed that GZMB was knocked down in tumor tissues of the SMURF1 group. + CD8 + The proportion of T cells increased significantly ( Figure 6 Simultaneously, IFN-γ expression levels were detected, and CD8 expression in the shSMURF1 group was also assessed. + The proportion of IFN-γ positive cells in T cells increased significantly ( Figure 7 The above results demonstrate that knocking down SMURF1 not only improves CD8 + The increased number of tumor-infiltrating T cells, along with elevated expression levels of the cytotoxic molecule GZMB and the cytokine IFN-γ, indicates that CD8+... + The immune activity of T cells is enhanced.
[0049] (II) Results of the A01 drug treatment experiment
[0050] In a Lewis lung cancer C57BL / 6 mouse xenograft model, the SMURF1 inhibitor A01 was administered. Results showed that the tumor volume growth rate was significantly slowed in the A01-treated group, and the endpoint tumor weight was significantly reduced. Figure 9 The mice's body weight remained stable, and there was no statistically significant difference between the groups. Figure 8 This indicates that the dose of A01 did not cause significant systemic toxicity.
[0051] Further flow cytometry analysis of the tumor tissue revealed that CD8+ was present in the tumor tissue of the A01 treatment group. + The proportion of T cell infiltration was significantly higher than that in the control group. Figure 10 (This suggests that A01 can promote CD8) + T cells enter the tumor microenvironment. To assess CD8... + The functional status of T cells was assessed, and effector markers in tumor tissue were detected. Results showed that GZMB in the A01 treatment group... + CD8 + The proportion of T cells increased significantly. Figure 11 ), and IFN-γ + CD8 + The proportion of T cells also increased significantly. Figure 12 This indicates that CD8 is processed by A01. + The cytotoxicity and immune activation levels of T cells were enhanced. Further protein expression analysis of tumor tissues showed that the protein expression levels of downstream molecules STAT1, CXCL9, and CXCL10 were significantly increased in the A01 treatment group. Figure 13(A~B). Furthermore, when SMURF1 was knocked down, the expression of STAT1, pSTAT1, and CXCL9 / CXCL10 was significantly increased, but this upward trend was reversed upon the addition of Fludarabine. Figure 13 (C~D). This indicates that inhibiting SMURF1 can activate STAT1 signaling, promote the expression of chemokines CXCL9 and CXCL10, thereby enhancing CD8. + T cell recruitment.
[0052] In addition, to verify whether the tumor-suppressive effect of A01 depends on CD8 + T cells, CD8 + T cell exhaustion assay. Results showed that in unexhausted CD8+ cells... + In the presence of T cells, the tumor volume and endpoint tumor weight in mice with knocked-down SMURF1 (shSMURF1+IgG) were significantly lower than those in the control group (shctrl+IgG), indicating that SMURF1 inhibition can significantly suppress tumor growth. However, when CD8... + T cells are cleared by antibodies (Ctrl+anti-CD8) + T, shSMURF1+anti-CD8 + T), both groups had significantly higher tumor volume and weight than the unexhausted group, and the difference between the two groups was not significant. Figure 14 This result indicates that in CD8 + Under conditions of T cell depletion, the tumor-suppressive effect was weakened or eliminated regardless of whether SMURF1 was knocked down, suggesting that the anti-tumor effect of SMURF1 inhibition is CD8-dependent. + The presence of T cells.
[0053] (III) Results of the A01 combined with PD-1 inhibitor treatment experiment Tumor growth curves and endpoint weight analysis showed that both A01 and PD-1 inhibitors, used alone, significantly inhibited tumor growth. The combined use of both further enhanced the tumor-suppressing effect, with tumor volume and weight significantly lower than both the single-drug group and the control group. This indicates that A01 can effectively improve the anti-tumor efficacy of PD-1 inhibitors. Figure 15 ).
[0054] Flow cytometry analysis of tumor tissue showed that A01 treatment could increase intratumoral CD8 levels. + T cell infiltration and increased effector readings such as GZMB and IFN-γ; combination therapy on the aforementioned CD8 + The relevant readings continued to improve, and correspondingly stronger in vivo tumor suppression endpoints were achieved. Figures 16-18 ). Combined with the aforementioned CD8 + The T-cell function-dependent validation results show that the combination regimen ensures CD8+ While T cell counts and functional readings are increasing, better overall tumor control has been achieved.
[0055] It should be noted that the effects of PD-1 inhibitors depend on the presence of CD8 receptors in the tumor microenvironment that can recognize tumor cells. + T cells, blocking PD-1 / PD-L1 alone can only relieve T cell suppression, but it is difficult to exert a significant anti-tumor effect when there is insufficient CD8⁺ T cell infiltration; A01 can increase CD8 in tumor tissue. + While increasing the number of T cells is important, their individual effect is limited if T cells cannot effectively recognize tumors. Therefore, when A01 is used in combination with PD-1 inhibitors, it can increase CD8+ levels. + The level of T cell infiltration, on the other hand, enables them to effectively recognize and attack tumor cells, thereby synergistically producing a significantly stronger in vivo tumor-suppressing effect than single drugs.
[0056] Obviously, the above embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the implementation of the present invention. Those skilled in the art can make other variations or modifications based on the above description. It is neither necessary nor possible to exhaustively describe all embodiments here. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the scope of protection of the claims of the present invention.
Claims
1. An application of an SMURF1 inhibitor, characterized in that, Preparation of CD8 for regulating the tumor immune microenvironment + Drugs that induce T-cell infiltration.
2. The application of the SMURF1 inhibitor according to claim 1, characterized in that, This is used to prepare drugs that regulate STAT1 protein levels and the expression of CXCL9 and CXCL10 chemokines.
3. The application of the SMURF1 inhibitor according to claim 1, characterized in that, Drugs used to prepare antitumor immune responses that enhance PD-1 and / or its ligand PD-L1 inhibitors.
4. The application of the SMURF1 inhibitor according to claim 1, characterized in that, This is used to prepare immunotherapeutic drugs for tumors associated with upregulated or abnormal SMURF1 expression and activity.
5. A synergistic immune composition, characterized in that, This includes SMURF1 inhibitors, PD-1 and / or their ligand PD-L1 inhibitors.
6. The synergistic immune composition according to claim 5, characterized in that, The mass ratio of SMURF1 inhibitor to PD-1 and / or its ligand PD-L1 inhibitor is 1:10~2000.
7. The use of the synergistic immune composition according to any one of claims 5-6, characterized in that, Used to prepare CD8 for regulating the tumor immune microenvironment + Drugs that induce T-cell infiltration.
8. The synergistic immune composition according to claim 7, characterized in that, This is used to prepare drugs that regulate STAT1 protein levels and the expression of CXCL9 and CXCL10 chemokines.
9. The synergistic immune composition according to claim 7, characterized in that, Used to prepare drugs that inhibit tumor growth.
10. The synergistic immune composition according to claim 9, characterized in that, The tumors were associated with upregulated SMURF1 expression or abnormal activity.