YTHDF2 in peritumoral hepatocytes mediates chemotherapy-induced antitumor immune responses through CX3CL1-mediated CD8+ T cell recruitment

作者：Zhenyun Yang, Xin Wang, Yizhen Fu, Weijie Wu, Zili Hu, Qingyang Lin, Wei Peng, Yangxun Pan, Juncheng Wang, Jinbin Chen, Dandan Hu, Zhongguo Zhou, Li Xu, Yaojun Zhang, Jiajie Hou, Minshan Chen · 发表于：Molecular Cancer · 年份：2024 · DOI：10.1186/s12943-024-02097-6 · 被引用次数：31 · 研究领域：Hepatocellular Carcinoma Treatment and Prognosis、Cancer Immunotherapy and Biomarkers、Cholangiocarcinoma and Gallbladder Cancer Studies

Peritumoral hepatocytes are critical components of the liver cancer microenvironment, However, the role of peritumoral hepatocytes in the local tumor immune interface and the underlying molecular mechanisms have not been elucidated. YTHDF2, an RNA N 6 -methyladenosine (m 6 A) reader, is critical for liver tumor progression. The function and regulatory roles of YTHDF2 in peritumoral hepatocytes are unknown. This study demonstrated that oxaliplatin (OXA) upregulated m 6 A modification and YTHDF2 expression in hepatocytes. Studies using tumor-bearing liver-specific Ythdf2 knockout mice revealed that hepatocyte YTHDF2 suppresses liver tumor growth through CD8 + T cell recruitment and activation. Additionally, YTHDF2 mediated the response to immunotherapy. Mechanistically, OXA upregulated YTHDF2 expression by activating the cGAS-STING signaling pathway and consequently enhanced the therapeutic outcomes of immunotherapeutic interventions. Ythdf2 stabilized Cx3cl1 transcripts in an m 6 A-dependent manner, regulating the interplay between CD8 + T cells and the progression of liver malignancies. Thus, this study elucidated the novel role of hepatocyte YTHDF2, which promotes therapy-induced antitumor immune responses in the liver. The findings of this study provide valuable insights into the mechanism underlying the therapeutic benefits of targeting YTHDF2.