E-twenty-six-specific sequence variant 5 (ETV5) facilitates hepatocellular carcinoma progression and metastasis through enhancing polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC)-mediated immunosuppression

作者：Zerui Zhang, Wenjie Huang, Dian Hu, Junqing Jiang, Jiaqian Zhang, Zhangfan Wu, Junjie Wen, Xiangyuan Luo, Yijun Wang, Mengyu Sun, Siwen Li, Yufei Wang, Danfei Liu, Xiaoping Chen, Bixiang Zhang, Huifang Liang, Yiwei Li, Bi‐Feng Liu, Shuai Wang, Xiao Xu, Yongzhan Nie, Kaichun Wu, Daiming Fan, Limin Xia · 发表于：Gut · 年份：2025 · DOI：10.1136/gutjnl-2024-333944 · 被引用次数：27 · 研究领域：Immune cells in cancer、Cancer Immunotherapy and Biomarkers、Ferroptosis and cancer prognosis

Background Despite the success of immune checkpoint blockade, a lack of understanding of the hepatocellular carcinoma (HCC) immune microenvironment impedes its development. Objective We aim to elucidate the essential function of E-twenty-six-specific sequence variant 5 (ETV5) in regulating the immune microenvironment in HCC. Design Humanised mouse models, murine orthotopic models and diethylnitrosamine/carbon tetrachloride (DEN/CCl 4 )-induced HCC models were used to examine the function of ETV5. The downstream targets of ETV5 were screened using chromatin immunoprecipitation sequencing, CUT&Tag and RNA sequencing. Immune cells were examined using flow cytometry and immunofluorescence. S100 calcium-binding protein A9 (S100A9) was targeted by neutralising antibodies. Results Overexpression of ETV5 in HCC cells facilitated HCC metastasis and immune escape by recruiting and enhancing the immunosuppressive capabilities of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Mechanistically, ETV5 transactivated programmed death ligand 1 (PD-L1) and S100A9 expression. Inhibition of S100A9 or myeloid-specific knockout of toll-like receptor 4 (TLR4)/receptor for advanced glycation endproducts (RAGE), the receptors of S100A9, impeded ETV5-induced PMN-MDSC recruitment. Meanwhile, S100A9 within the tumour microenvironment elevated ETV5 expression via the extracellular signal-regulated kinase (ERK)/nuclear factor-kappa B pathway. Additionally, ETV5 transcriptionally upregu...