表观转录因子 PCIF1 协调 CD8(+) T 细胞铁死亡和激活以控制抗肿瘤免疫

T cell-based immunotherapies have revolutionized cancer treatment, yet durable responses remain elusive.

Here we show that PCIF1, an RNA N 6 2'-O-dimethyladenosine (m 6 A m ) 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 m 6 A m -sequencing analyses pinpoint that Pcif1 KO elevates m 6 A m -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.