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Tumor-intrinsic ETV5 expression promotes PMN-MDSC-mediated immune evasion and immune checkpoint inhibitor resistance by activating the JAK2/STAT3/CCL2 axis

Oncogene volume 45, pages 774–789 (2026)Cite this article

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Abstract

Immunotherapy remains ineffective for a wide variety of solid tumors due to the existence of tumor immune evasion. Although the transcription factor ETV5 is recognized for its oncogenic roles in tumor progression, its role in remodeling the immunosuppressive microenvironment remains largely unexplored. Here, we reveal that tumor-intrinsic ETV5 drives immune evasion and immune checkpoint inhibitor (ICI) resistance by enhancing the expansion and recruitment of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Genetic silencing of ETV5 in murine tumor models suppressed PMN-MDSCs differentiation from myeloid progenitors, reduced their tumor infiltration, and attenuated immunosuppressive function, resulting in enhanced cytotoxic T cell activity and delayed tumor progression. Mechanistically, ETV5 directly binds to the JH1 domain of JAK2, inducing its dimerization and phosphorylation, which activates STAT3 to transcriptionally upregulate CCL2 and recruit PMN-MDSCs. Therapeutically, ETV5 ablation synergized with anti-PD-L1 therapy to enhance tumor control, mirroring clinical observations where high ETV5 expression predicted immunotherapy resistance. Our study uncovers a non-canonical, transcription-independent role of ETV5 in orchestrating the JAK2/STAT3/CCL2 axis to sustain PMN-MDSC-mediated immune evasion, proposing ETV5 as a druggable target to overcome ICI resistance in solid tumors.

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Fig. 1: ETV5 is pro-oncogenic and associated with tumor immune suppression.
Fig. 2: ETV5 deficiency reshapes the tumor immune microenvironment.
Fig. 3: ETV5 deficiency bolsters antitumor immunity by reducing PMN-MDSCs and inhibiting their function.
Fig. 4: ETV5 promotes the expansion of myeloid precursor cells in bone marrow and spleen.
Fig. 5: ETV5-induced CCL2 contributes to PMN-MDSC expansion and recruitment.
Fig. 6: ETV5 promotes the phosphorylation of JAK2 and STAT3, thereby increasing the transcription of CCL2.
Fig. 7: ETV5 deficiency enhances the ICI therapy efficacy in vivo.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors sincerely acknowledge the invaluable support and assistance provided by Professor Lian Zhexiong from Guangdong Provincial People’s Hospital during the entire experimental process. The working model was created with FigDraw.

Funding

This work was supported by grants from National Natural Science Foundation of China (82173236), Guangzhou High-level Key Clinical Specialty Construction Project (No.9), Guangzhou Science and Technology Planning Project (202206080008), Guangzhou Initiative for Basic and Applied Basic Research: The “Kick-start” Initiative for Young Doctors (2024A04J4009), National Natural Science Foundation of China (82003125), Guangzhou Initiative for Basic and Applied Basic Research: Young Doctoral Scientist Program (202102021249), Guangzhou Collaborative Grant for Basic Research (202201020269).

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Authors and Affiliations

  1. Department of General Surgery, Guangzhou First People’s Hospital, Institute of Digestive Diseases, South China University of Technology, Guangzhou, Guangdong, China

    Ting-Ting Yin, Ping Yang, Yuan Yao & Jie Cao

  2. Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China

    Meng-Xing Huang, Meng-Chu Liu & Pan-Yue Luo

  3. Medical Research Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China

    Tian-tian Da & Chuan Huang

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TTY was responsible for designing the research, acquiring and analyzing data, drafting and editing the manuscript. MXH, MCL, PYL, TD, and CH assisted with the experiments. PY contributed to the supervision of the manuscript. YY was responsible for analyzing data, drafting, and editing the manuscript. JC was responsible for designing the research and supervising the manuscript.

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Correspondence to Ting-Ting Yin, Yuan Yao or Jie Cao.

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Yin, TT., Huang, MX., Liu, MC. et al. Tumor-intrinsic ETV5 expression promotes PMN-MDSC-mediated immune evasion and immune checkpoint inhibitor resistance by activating the JAK2/STAT3/CCL2 axis. Oncogene 45, 774–789 (2026). https://doi.org/10.1038/s41388-026-03686-z

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