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<p>T cell-based immunotherapies have revolutionized cancer treatment, yet durable responses remain elusive. Here we show that PCIF1, an RNA <i>N</i><sup>6</sup> 2′-<i>O</i>-dimethyladenosine (m<sup>6</sup>A<sub>m</sub>) methyltransferase, negatively regulates CD8<sup>+</sup> T cell antitumor responses. Whole-body or T cell-specific <i>Pcif1</i> knockout (KO) reduced tumor growth in mice. Single-cell RNA sequencing shows an increase in the number of tumor-infiltrating cytotoxic CD8<sup>+</sup> T cells in <i>Pcif1</i>-deficient mice. Mechanistically, proteomic and m<sup>6</sup>A<sub>m</sub>-sequencing analyses pinpoint that <i>Pcif1</i> KO elevates m<sup>6</sup>A<sub>m</sub>-modified targets, specifically ferroptosis suppressor genes (<i>Fth1</i>, <i>Slc3a2</i>), and the T cell activation gene <i>Cd69</i>, imparting resistance to ferroptosis and enhancing CD8<sup>+</sup> T cell activation. Of note, <i>Pcif1</i>-deficient mice had enhanced responses to anti-PD-1 immunotherapy, and <i>Pcif1</i> 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<sup>+</sup> T cell activation and targeting PCIF1 is a promising strategy to boost antitumor immunity.</p>

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

  • 期刊论文

  • 发表日期：

    2025年1月6日

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  • Bolin Xiang,
  • Meiling Zhang,
  • Kai Li,
  • Zijian Zhang,
  • Yutong Liu,
  • Minling Gao,
  • Xiyong Wang,
  • Xiangling Xiao,
  • Yishuang Sun,
  • Chuan He,
  • Jie Shi,
  • Hongzeng Fan,
  • Xixin Xing,
  • Gaoshan Xu,
  • Yingmeng Yao,
  • Gang Chen,
  • Haichuan Zhu,
  • Chengqi Yi,
  • Jinfang Zhang

摘要

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.