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USP14-IMP2-CXCL2 axis in tumor-associated macrophages facilitates resistance to anti-PD-1 therapy in gastric cancer by recruiting myeloid-derived suppressor cells

Oncogene volume 44, pages 2413–2426 (2025)Cite this article

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Abstract

Resistance to anti-PD-1 therapy remains a significant challenge in gastric cancer (GC) treatment. Here, we revealed that the USP14-IMP2-CXCL2 axis in tumor-associated macrophages (TAMs) drove resistance by recruiting myeloid-derived suppressor cells (MDSCs). Endoscopic biopsy samples were obtained from patients with inoperable GC who were candidates for anti-PD-1 therapy. Single-cell RNA sequencing (scRNA-seq) analysis showed a higher prevalence of USP14+ TAMs in therapy-resistant cases, where USP14 was linked to the immunosuppressive phenotype of TAMs. Clinically, GC samples with elevated USP14+ TAM infiltration exhibited decreased CD8+ T cell presence and increased MDSC infiltration. In vivo experiments further confirmed that USP14+ TAMs facilitated resistance to anti-PD-1 therapy in GC, reduced the infiltration of CD8+ T cells, and significantly increased the infiltration of MDSCs. In particular, USP14+ TAMs markedly enhanced the recruitment of MDSCs into the GC microenvironment through the secretion of CXCL2. Mechanistically, USP14 stabilized the m6A reader IMP2 through deubiquitination, thus enhancing CXCL2 expression and secretion. Conversely, the E3 ligase RNF40 facilitated IMP2 degradation via increasing its ubiquitination, with USP14 and RNF40 dynamically balancing IMP2’s protein abundance. Furthermore, animal experiments demonstrated that targeted intervention of USP14 markedly enhanced the sensitivity of GC to anti-PD-1 therapy. This study provided a comprehensive exploration of USP14’s oncogenic roles in TAMs, suggesting a novel strategy to enhance the efficacy of anti-PD-1 therapy by inhibiting the USP14/IMP2/CXCL2 signaling axis in GC.

The sc-RNA analysis revealed that infiltration of USP14+ TAM was significantly higher in anti-PD-1 resistant GC compared to anti-PD-1 sensitive GC (top). USP14 stabilized IMP2 protein in tumor-associated macrophages (middle-left), leading to recruitment of MDSCs into GC microenvironment through secretion of CXCL2 (middle-right), thus reducing the infiltration of CD8+ T cells and facilitating the resistance to anti-PD-1 therapy in GC (bottom). Comment: Dear editors, in formally published articles, figure legends could be placed beneath their corresponding figures. In this version, is this arrangement adopted for the sake of convenience during the proofreading process? If so, we understand and accept this layout.

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Fig. 1: Cellular landscape of GC samples in the resistant and sensitive groups before initiation of anti-PD-1 therapy.
Fig. 2: USP14+ TAMs exhibited increased infiltration in the anti-PD-1 resistant group.
Fig. 3: USP14+ TAMs facilitated resistance to anti-PD-1 therapy and decreased infiltration of CD8+ T cells.
Fig. 4: USP14+ TAMs increased recruitment of MDSCs into GC microenvironment by secretion of CXCL2.
Fig. 5: USP14 interacted with and deubiquitinated IMP2 protein.
Fig. 6: Dynamic equilibrium between USP14-mediated stabilization and RNF40-induced degradation in regulating the IMP2 protein.
Fig. 7: Role of IMP2 in the USP14-mediated regulation of CXCL2.
Fig. 8: Inhibition of USP14 increased sensitivity to anti-PD-1 therapy in GC.

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Data availability

The single-cell RNA sequencing data (FUSCC Cohort 1) have been deposited in National Omics Data Encyclopedia (http://www.biosino.org/node): OEZ00017591. The readers can also obtained these data through contacting the corresponding author, Prof. Yu Zhang (zyu722320@163.com). Other materials in current study is available from the corresponding author upon reasonable requests.

Code availability

Our code used in this study can be available from the corresponding authors upon reasonable requests.

References

  1. Wang Z, Han W, Xue F, Zhao Y, Wu P, Chen Y, et al. Nationwide gastric cancer prevention in China, 2021-2035: a decision analysis on effect, affordability and cost-effectiveness optimisation. Gut. 2022;71:2391–2400.

    Article  PubMed  Google Scholar 

  2. You L, Dou Y, Zhang Y, Xiao H, Lv H, Wei GH, et al. SDC2 Stabilization by USP14 Promotes Gastric Cancer Progression through Co-option of PDK1. Int J Biol Sci. 2023;19:3483–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Xue W, Xu C, Zhang K, Cui L, Huang X, Nan Y, et al. Enhancing antitumor efficacy of CLDN18.2-directed antibody-drug conjugates through autophagy inhibition in gastric cancer. Cell Death Discov. 2024;10:393.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Janjigian YY, Shitara K, Moehler M, Garrido M, Salman P, Shen L, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021;398:27–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Rha SY, Oh DY, Yanez P, Bai Y, Ryu MH, Lee J, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2023;24:1181–95.

    Article  CAS  PubMed  Google Scholar 

  6. Xu J, Jiang H, Pan Y, Gu K, Cang S, Han L, et al. Sintilimab Plus Chemotherapy for Unresectable Gastric or Gastroesophageal Junction Cancer: The ORIENT-16 Randomized Clinical Trial. JAMA. 2023;330:2064–74.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Yukami H, Kawazoe A, Lin YT, Koyama S, Fukuoka S, Hara H, et al. Updated Efficacy Outcomes of Anti-PD-1 Antibodies plus Multikinase Inhibitors for Patients with Advanced Gastric Cancer with or without Liver Metastases in Clinical Trials. Clin Cancer Res. 2022;28:3480–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kwon M, An M, Klempner SJ, Lee H, Kim KM, Sa JK, et al. Determinants of Response and Intrinsic Resistance to PD-1 Blockade in Microsatellite Instability-High Gastric Cancer. Cancer Discov. 2021;11:2168–85.

    Article  CAS  PubMed  Google Scholar 

  9. Bain CC, Mowat AM. Macrophages in intestinal homeostasis and inflammation. Immunol Rev. 2014;260:102–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Li J, Sun J, Zeng Z, Liu Z, Ma M, Zheng Z, et al. Tumour-associated macrophages in gastric cancer: From function and mechanism to application. Clin Transl Med. 2023;13:e1386.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lv K, Sun M, Fang H, Wang J, Lin C, Liu H et al. Targeting myeloid checkpoint Siglec-10 reactivates antitumor immunity and improves anti-programmed cell death 1 efficacy in gastric cancer. J Immunother Cancer. 2023;11:e007669.

  12. Eissmann MF, Dijkstra C, Jarnicki A, Phesse T, Brunnberg J, Poh AR, et al. IL-33-mediated mast cell activation promotes gastric cancer through macrophage mobilization. Nat Commun. 2019;10:2735.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Wang YC, Wang X, Yu J, Ma F, Li Z, Zhou Y, et al. Targeting monoamine oxidase A-regulated tumor-associated macrophage polarization for cancer immunotherapy. Nat Commun. 2021;12:3530.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Dong X, Fan J, Xie W, Wu X, Wei J, He Z, et al. Efficacy evaluation of chimeric antigen receptor-modified human peritoneal macrophages in the treatment of gastric cancer. Br J Cancer. 2023;129:551–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Candido JB, Morton JP, Bailey P, Campbell AD, Karim SA, Jamieson T, et al. CSF1R(+) Macrophages Sustain Pancreatic Tumor Growth through T Cell Suppression and Maintenance of Key Gene Programs that Define the Squamous Subtype. Cell Rep. 2018;23:1448–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Veglia F, Sanseviero E, Gabrilovich DI. Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity. Nat Rev Immunol. 2021;21:485–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Liu X, Tang R, Xu J, Tan Z, Liang C, Meng Q, et al. CRIP1 fosters MDSC trafficking and resets tumour microenvironment via facilitating NF-kappaB/p65 nuclear translocation in pancreatic ductal adenocarcinoma. Gut. 2023;72:2329–43.

    Article  CAS  PubMed  Google Scholar 

  18. Bao Y, Zhai J, Chen H, Wong CC, Liang C, Ding Y, et al. Targeting m(6)A reader YTHDF1 augments antitumour immunity and boosts anti-PD-1 efficacy in colorectal cancer. Gut. 2023;72:1497–509.

    Article  CAS  PubMed  Google Scholar 

  19. Liao W, Overman MJ, Boutin AT, Shang X, Zhao D, Dey P, et al. KRAS-IRF2 Axis Drives Immune Suppression and Immune Therapy Resistance in Colorectal Cancer. Cancer Cell. 2019;35:559–572.e557.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Huang B, Pan PY, Li Q, Sato AI, Levy DE, Bromberg J, et al. Gr-1+CD115+ immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T-cell anergy in tumor-bearing host. Cancer Res. 2006;66:1123–31.

    Article  CAS  PubMed  Google Scholar 

  21. Li N, Kang Y, Wang L, Huff S, Tang R, Hui H, et al. ALKBH5 regulates anti-PD-1 therapy response by modulating lactate and suppressive immune cell accumulation in tumor microenvironment. Proc Natl Acad Sci USA. 2020;117:20159–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Nagarsheth N, Wicha MS, Zou W. Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. Nat Rev Immunol. 2017;17:559–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Schiwon M, Weisheit C, Franken L, Gutweiler S, Dixit A, Meyer-Schwesinger C, et al. Crosstalk between sentinel and helper macrophages permits neutrophil migration into infected uroepithelium. Cell. 2014;156:456–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Wang X, Tokheim C, Gu SS, Wang B, Tang Q, Li Y, et al. In vivo CRISPR screens identify the E3 ligase Cop1 as a modulator of macrophage infiltration and cancer immunotherapy target. Cell. 2021;184:5357–5374.e5322.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Shi D, Wu X, Jian Y, Wang J, Huang C, Mo S, et al. USP14 promotes tryptophan metabolism and immune suppression by stabilizing IDO1 in colorectal cancer. Nat Commun. 2022;13:5644.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zhao C, Gong J, Bai Y, Yin T, Zhou M, Pan S, et al. A self-amplifying USP14-TAZ loop drives the progression and liver metastasis of pancreatic ductal adenocarcinoma. Cell Death Differ. 2023;30:1–15.

    Article  PubMed  Google Scholar 

  27. Lange SM, Armstrong LA, Kulathu Y. Deubiquitinases: From mechanisms to their inhibition by small molecules. Mol Cell. 2022;82:15–29.

    Article  CAS  PubMed  Google Scholar 

  28. Zhang S, Zou S, Yin D, Zhao L, Finley D, Wu Z, et al. USP14-regulated allostery of the human proteasome by time-resolved cryo-EM. Nature. 2022;605:567–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Yang J, Xu P, Chen Z, Zhang X, Xia Y, Fang L, et al. N6-methyadenosine modified SUV39H2 regulates homologous recombination through epigenetic repression of DUSP6 in gastric cancer. Cancer Lett. 2023;558:216092.

    Article  CAS  PubMed  Google Scholar 

  30. Weng H, Huang F, Yu Z, Chen Z, Prince E, Kang Y, et al. The m(6)A reader IGF2BP2 regulates glutamine metabolism and represents a therapeutic target in acute myeloid leukemia. Cancer Cell. 2022;40:1566–82 e1510.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Huang H, Weng H, Sun W, Qin X, Shi H, Wu H, et al. Recognition of RNA N(6)-methyladenosine by IGF2BP proteins enhances mRNA stability and translation. Nat Cell Biol. 2018;20:285–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kessler SM, Pokorny J, Zimmer V, Laggai S, Lammert F, Bohle RM, et al. IGF2 mRNA binding protein p62/IMP2-2 in hepatocellular carcinoma: antiapoptotic action is independent of IGF2/PI3K signaling. Am J Physiol Gastrointest Liver Physiol. 2013;304:G328–336.

    Article  CAS  PubMed  Google Scholar 

  33. Allen WL, Jithesh PV, Oliver GR, Proutski I, Longley DB, Lenz HJ, et al. The colorectal cancer disease-specific transcriptome may facilitate the discovery of more biologically and clinically relevant information. BMC Cancer. 2010;10:687.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Simon Y, Kessler SM, Bohle RM, Haybaeck J, Kiemer AK. The insulin-like growth factor 2 (IGF2) mRNA-binding protein p62/IGF2BP2-2 as a promoter of NAFLD and HCC? Gut. 2014;63:861–3.

    Article  PubMed  Google Scholar 

  35. Kessler SM, Laggai S, Barghash A, Schultheiss CS, Lederer E, Artl M, et al. IMP2/p62 induces genomic instability and an aggressive hepatocellular carcinoma phenotype. Cell Death Dis. 2015;6:e1894.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Valverde R, Edwards L, Regan L. Structure and function of KH domains. FEBS J. 2008;275:2712–26.

    Article  CAS  PubMed  Google Scholar 

  37. Cao T, Zhang W, Wang Q, Wang C, Ma W, Zhang C et al. Cancer SLC6A6-mediated taurine uptake transactivates immune checkpoint genes and induces exhaustion in CD8(+) T cells. Cell. 2024;187:2288–304.e27.

  38. Yao Y, Liu Q, Adrianto I, Wu X, Glassbrook J, Khalasawi N, et al. Histone deacetylase 3 controls lung alveolar macrophage development and homeostasis. Nat Commun. 2020;11:3822.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Chen J, Yao Y, Gong C, Yu F, Su S, Chen J, et al. CCL18 from tumor-associated macrophages promotes breast cancer metastasis via PITPNM3. Cancer Cell. 2011;19:541–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Tsvetkov P, Detappe A, Cai K, Keys HR, Brune Z, Ying W, et al. Mitochondrial metabolism promotes adaptation to proteotoxic stress. Nat Chem Biol. 2019;15:681–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Willenborg S, Sanin DE, Jais A, Ding X, Ulas T, Nuchel J, et al. Mitochondrial metabolism coordinates stage-specific repair processes in macrophages during wound healing. Cell Metab. 2021;33:2398–414 e2399.

    Article  CAS  PubMed  Google Scholar 

  42. Chaib S, Lopez-Dominguez JA, Lalinde-Gutierrez M, Prats N, Marin I, Boix O, et al. The efficacy of chemotherapy is limited by intratumoral senescent cells expressing PD-L2. Nat Cancer. 2024;5:448–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Xie M, Lin Z, Ji X, Luo X, Zhang Z, Sun M, et al. FGF19/FGFR4-mediated elevation of ETV4 facilitates hepatocellular carcinoma metastasis by upregulating PD-L1 and CCL2. J Hepatol. 2023;79:109–25.

    Article  CAS  PubMed  Google Scholar 

  44. Brina D, Ponzoni A, Troiani M, Cali B, Pasquini E, Attanasio G, et al. The Akt/mTOR and MNK/eIF4E pathways rewire the prostate cancer translatome to secrete HGF, SPP1 and BGN and recruit suppressive myeloid cells. Nat Cancer. 2023;4:1102–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kumar V, Ramnarayanan K, Sundar R, Padmanabhan N, Srivastava S, Koiwa M, et al. Single-Cell Atlas of Lineage States, Tumor Microenvironment, and Subtype-Specific Expression Programs in Gastric Cancer. Cancer Discov. 2022;12:670–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Qiu MZ, Oh DY, Kato K, Arkenau T, Tabernero J, Correa MC, et al. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first line treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma: RATIONALE-305 randomised, double blind, phase 3 trial. BMJ. 2024;385:e078876.

    Article  CAS  PubMed  Google Scholar 

  47. Chen Y, Jia K, Sun Y, Zhang C, Li Y, Zhang L, et al. Predicting response to immunotherapy in gastric cancer via multi-dimensional analyses of the tumour immune microenvironment. Nat Commun. 2022;13:4851.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Bell HN, Zou W. Beyond the Barrier: Unraveling the Mechanisms of Immunotherapy Resistance. Annu Rev Immunol. 2024;42:521–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kono K, Nakajima S, Mimura K. Biomarker-oriented chemo-immunotherapy for advanced gastric cancer. Int J Clin Oncol. 2024;29:865–72.

    Article  PubMed  Google Scholar 

  50. Chong X, Madeti Y, Cai J, Li W, Cong L, Lu J, et al. Recent developments in immunotherapy for gastrointestinal tract cancers. J Hematol Oncol. 2024;17:65.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Xiang J, Zhang N, Du A, Li J, Luo M, Wang Y, et al. A Ubiquitin-Dependent Switch on MEF2D Senses Pro-Metastatic Niche Signals to Facilitate Intrahepatic Metastasis of Liver Cancer. Adv Sci. 2023;10:e2305550.

    Article  Google Scholar 

  52. Liu D, Li M, Zhao Z, Zhou L, Zhi F, Guo Z et al. Targeting the TRIM14/USP14 Axis Enhances Immunotherapy Efficacy by Inducing Autophagic Degradation of PD-L1. Cancer Res. 2024;84:2806–19.

  53. Rowinsky EK, Paner A, Berdeja JG, Paba-Prada C, Venugopal P, Porkka K, et al. Phase 1 study of the protein deubiquitinase inhibitor VLX1570 in patients with relapsed and/or refractory multiple myeloma. Invest N Drugs. 2020;38:1448–53.

    Article  CAS  Google Scholar 

  54. Liu B, Chen J, Zhang S. Emerging role of ubiquitin-specific protease 14 in oncogenesis and development of tumor: Therapeutic implication. Life Sci. 2019;239:116875.

    Article  CAS  PubMed  Google Scholar 

  55. Wang J, Chen L, Qiang P. The role of IGF2BP2, an m6A reader gene, in human metabolic diseases and cancers. Cancer Cell Int. 2021;21:99.

    Article  PubMed  PubMed Central  Google Scholar 

  56. O’Reilly ME, Ho S, Coronel J, Zhu L, Liu W, Xue C, et al. linc-ADAIN, a human adipose lincRNA, regulates adipogenesis by modulating KLF5 and IL-8 mRNA stability. Cell Rep. 2024;43:114240.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Arshad J, Rao A, Repp ML, Rao R, Wu C, Merchant JL. Myeloid-Derived Suppressor Cells: Therapeutic Target for Gastrointestinal Cancers. Int J Mol Sci. 2024;25:2985.

  58. Zhou X, Fang D, Liu H, Ou X, Zhang C, Zhao Z, et al. PMN-MDSCs accumulation induced by CXCL1 promotes CD8(+) T cells exhaustion in gastric cancer. Cancer Lett. 2022;532:215598.

    Article  CAS  PubMed  Google Scholar 

  59. Shitara K, Di Bartolomeo M, Mandala M, Ryu MH, Caglevic C, Olesinski T et al. Association between gene expression signatures and clinical outcomes of pembrolizumab versus paclitaxel in advanced gastric cancer: exploratory analysis from the randomized, controlled, phase III KEYNOTE-061 trial. J Immunother Cancer. 2023;11:e006920.

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Acknowledgements

We express our gratitude to Prof. Gong-Hong Wei, chair of the Department of Molecular Biology and Biochemistry, Fudan University, Shanghai, and Prof. Dazhi Xu, chair of the Department of Gastric Surgery, Fudan University Shanghai Cancer Center, for thier very detailed and useful suggestions on this study.

Funding

This study was supported by research funding of FUSCC (SCIP-2023146) and by the National Natural Science Foundation of China (No. 32200745).

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Author notes

  1. These authors contributed equally: Li You, Qian Wang, Tianxue Zhang, Hongwei Xiao.

Authors and Affiliations

  1. Department of Gastric Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China

    Li You & Yu Zhang

  2. Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China

    Qian Wang

  3. Yangpu Branch Campus, Shanghai Open University, Shanghai, 200082, China

    Tianxue Zhang

  4. Key Laboratory of Animal Embryo Engineering and Molecular Breeding of Hubei Province, Institute of Animal Husbandry and Veterinary, Hubei Academy of Agricultural Science, Wuhan, 430064, China

    Hongwei Xiao

  5. Department of Infectious Diseases, Shanghai East Hospital, Tongji University, Shanghai, 200120, China

    Mengjiao Lv

  6. Department of Pathology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China

    Hong Lv

  7. Department of General Surgery, The Shanghai Public Health Clinical Center, Fudan University, Shanghai, 200032, China

    Li Deng

  8. Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, School of Pharmacy, Fudan University, Shanghai, 201203, China

    Xuyao Zhang

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Contributions

Li You, Xuyao Zhang, and Yu Zhang designed the research. Li You, Qian Wang, Hongwei Xiao and Mengjiao Lv performed the experiments. Hong Lv assessed the immunohistochemical scores. Li You, Tianxue Zhang, Li Deng and Yu Zhang analyzed data and wrote the manuscript. Xuyao Zhang and Yu Zhang supervised the process of this study and revised manuscript. All authors read and approved the final manuscript.

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Correspondence to Xuyao Zhang or Yu Zhang.

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The authors declare no competing interests.

Ethics

Informed consent forms were signed by all GC patients enrolled in this study, and the study was approved by the Ethics Committee of Fudan University Shanghai Cancer Center (Approval No. 2012228-14). The animal experiments were also approved by the Ethics Committee of Fudan University Shanghai Cancer Center (Approval No. IACUC-2023301). Additionally, the care and handling of the animals were conducted in accordance with applicable animal welfare regulation.

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You, L., Wang, Q., Zhang, T. et al. USP14-IMP2-CXCL2 axis in tumor-associated macrophages facilitates resistance to anti-PD-1 therapy in gastric cancer by recruiting myeloid-derived suppressor cells. Oncogene 44, 2413–2426 (2025). https://doi.org/10.1038/s41388-025-03425-w

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