武汉大学张金方等研究人员合作发现，表观转录因子PCIF1协调CD8⁺ T细胞的铁死亡和激活来调控抗肿瘤免疫。2025年1月6日，《自然—免疫学》杂志在线发表了这一最新研究成果。

研究人员发现RNA N⁶ 2′-O-二甲基腺苷（m⁶A_m）甲基转移酶PCIF1负向调节CD8⁺ T细胞的抗肿瘤反应。全身或T细胞特异性Pcif1基因敲除（KO）能够减少小鼠的肿瘤生长。单细胞RNA测序显示，Pcif1缺失的小鼠中，肿瘤浸润性细胞毒性CD8⁺ T细胞的数量增加。

在机制上，蛋白质组学和m⁶A_m测序分析发现，Pcif1 KO提高了m⁶A_m修饰的靶基因，特别是铁死亡抑制基因（Fth1、Slc3a2）和T细胞激活基因Cd69，从而赋予T细胞对铁死亡的抵抗力并增强CD8⁺ T细胞的激活。

值得注意的是，Pcif1缺失的小鼠对抗PD-1免疫疗法的反应增强，Pcif1 KO嵌合抗原受体T细胞改善了肿瘤控制。在临床上，T细胞中低PCIF1表达的癌症患者对免疫疗法的反应更强。这些发现表明，PCIF1抑制CD8⁺ T细胞激活，靶向PCIF1是增强抗肿瘤免疫的有望策略。

研究人员表示，基于T细胞的免疫疗法已经彻底改变了癌症治疗，但持久的疗效仍然难以实现。

附：英文原文

Title: The epitranscriptional factor PCIF1 orchestrates CD8+ T cell ferroptosis and activation to control antitumor immunity

Author: 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

Issue&Volume: 2025-01-06

Abstract: T cell-based immunotherapies have revolutionized cancer treatment, yet durable responses remain elusive. Here we show that PCIF1, an RNA N6 2′-O-dimethyladenosine (m6Am) 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 m6Am-sequencing analyses pinpoint that Pcif1 KO elevates m6Am-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.

DOI: 10.1038/s41590-024-02047-w

Source: https://www.nature.com/articles/s41590-024-02047-w