Xiang Bolin, Zhang Meiling, Li Kai, Zhang Zijian, Liu Yutong, Gao Minling, Wang Xiyong, Xiao Xiangling, Sun Yishuang, He Chuan, Shi Jie, Fan Hongzeng, Xing Xixin, Xu Gaoshan, Yao Yingmeng, Chen Gang, Zhu Haichuan, Yi Chengqi, Zhang Jinfang
Department of Radiation and Medical Oncology, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Hubei Key Laboratory of Tumor Biological Behavior, Hubei Provincial Clinical Research Center for Cancer, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.
Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China.
Nat Immunol. 2025 Feb;26(2):252-264. doi: 10.1038/s41590-024-02047-w. Epub 2025 Jan 6.
T cell-based immunotherapies have revolutionized cancer treatment, yet durable responses remain elusive. Here we show that PCIF1, an RNA N 2'-O-dimethyladenosine (mA) methyltransferase, negatively regulates CD8 T cell antitumor responses. Whole-body or T cell-specific Pcif1 knockout (KO) reduced tumor growth in mice. Single-cell RNA sequencing shows an increase in the number of tumor-infiltrating cytotoxic CD8 T cells in Pcif1-deficient mice. Mechanistically, proteomic and mA-sequencing analyses pinpoint that Pcif1 KO elevates mA-modified targets, specifically ferroptosis suppressor genes (Fth1, Slc3a2), and the T cell activation gene Cd69, imparting resistance to ferroptosis and enhancing CD8 T cell activation. Of note, Pcif1-deficient mice had enhanced responses to anti-PD-1 immunotherapy, and Pcif1 KO chimeric antigen receptor T cells improved tumor control. Clinically, cancer patients with low PCIF1 expression in T cells have enhanced responses to immunotherapies. These findings suggest that PCIF1 suppresses CD8 T cell activation and targeting PCIF1 is a promising strategy to boost antitumor immunity.
基于T细胞的免疫疗法彻底改变了癌症治疗方式，但持久的反应仍然难以实现。在这里，我们表明，RNA N2'-O-二甲基腺苷（mA）甲基转移酶PCIF1对CD8 T细胞抗肿瘤反应具有负调控作用。全身或T细胞特异性Pcif1基因敲除（KO）可减少小鼠肿瘤生长。单细胞RNA测序显示，Pcif1基因缺陷小鼠中肿瘤浸润性细胞毒性CD8 T细胞数量增加。从机制上讲，蛋白质组学和mA测序分析指出，Pcif1基因敲除可提高mA修饰的靶点，特别是铁死亡抑制基因（Fth1、Slc3a2）和T细胞激活基因Cd69，赋予对铁死亡的抗性并增强CD8 T细胞激活。值得注意的是，Pcif1基因缺陷小鼠对抗PD-1免疫疗法的反应增强，Pcif1基因敲除的嵌合抗原受体T细胞改善了肿瘤控制。在临床上，T细胞中PCIF1表达低的癌症患者对免疫疗法的反应增强。这些发现表明，PCIF1抑制CD8 T细胞激活，靶向PCIF1是增强抗肿瘤免疫力的一种有前景的策略。
