Liang Manman, Yang Jianghua, Zhang Aiping, Zhong Na, Quan Bin, Wang Zijian, Zhao Wenying, Geng Biao, Gao Yufeng
Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
Department of Infectious Diseases, Yijishan Hospital, The First Affiliated Hospital of Wannan Medical College, Wuhu, 241000, Anhui, China.
Cancer Immunol Immunother. 2025 Mar 27;74(5):162. doi: 10.1007/s00262-025-04002-6.
RING finger protein 2 (RNF2) has been shown to promote tumor growth in various cancer types. However, the immune regulatory function of RNF2 in the tumor microenvironment is unclear. Here, we report that upregulation of RNF2 is positively correlated with the tumor burden and poor prognosis in hepatocellular carcinoma patients and fosters an immunosuppressive microenvironment with increased MDSCs recruitment, and reduced T cell activation. Mechanistically, RNF2 binds with TRAF2 and directly mediates K63-linked TRAF2 ubiquitination. This modification of TRAF2 enables NF-κB hyperactivation in tumor cells, which subsequently induces CXCL1 transcription to enhance MDSCs migration. Furthermore, RNF2 knockout improves responsiveness to anti-PD-1 therapy in immunocompetent mice, as evidenced by enhancing infiltration of CD8T cells into the tumor and a reduction in MDSC levels. Collectively, our experiments support that perturbing RNF2 and targeting MDSCs may afford therapeutic opportunities for hepatocellular carcinoma interception and prevention.
环指蛋白2（RNF2）已被证明在多种癌症类型中促进肿瘤生长。然而，RNF2在肿瘤微环境中的免疫调节功能尚不清楚。在此，我们报告RNF2的上调与肝细胞癌患者的肿瘤负荷和不良预后呈正相关，并促进免疫抑制微环境，增加髓源性抑制细胞（MDSCs）募集，降低T细胞活化。机制上，RNF2与TRAF2结合并直接介导K63连接的TRAF2泛素化。TRAF2的这种修饰使肿瘤细胞中的核因子κB（NF-κB）过度活化，随后诱导CXC趋化因子配体1（CXCL1）转录以增强MDSCs迁移。此外，RNF2基因敲除提高了免疫健全小鼠对抗程序性死亡蛋白1（PD-1）治疗的反应性，表现为增强CD8+T细胞向肿瘤内浸润以及降低MDSC水平。总体而言，我们的实验支持干扰RNF2并靶向MDSCs可能为肝细胞癌的拦截和预防提供治疗机会。
