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The epitranscriptional factor PCIF1 orchestrates CD8+ T cell ferroptosis and activation to govern anti-tumor immunity

ABSTRACT: T cell-based cancer immunotherapies have revolutionized cancer treatment, yet durable responses remain elusive. Here, we report that PCIF1, an RNA N6, 2’-O-dimethyladenosine (m6Am) methyltransferase, negatively regulates CD8+ T cell anti-tumor responses. Whole-body or T cell-specific Pcif1 knockout (KO) significantly reduces tumor growth in mice. Single-cell RNA sequencing reveals heightened tumor-infiltrating cytotoxic CD8+ T cells in Pcif1-deficient mice. Mechanistically, proteomic and m6Am-sequencing analyses pinpoint that Pcif1 KO elevates crucial m6Am-modified targets, specifically ferroptosis suppressor genes (Fth1, Slc3a2), and T cell activation gene Cd69, imparting resistance to ferroptosis and enhancing CD8+ T cell activation. Of note, Pcif1-deficient mice with tumors exhibit enhanced responses to anti-PD-1 immunotherapy, and Pcif1 KO CAR T cells demonstrate improved tumor control. Clinically, cancer patients with low PCIF1 expression in T cells exhibit enhanced responses to immunotherapies. These findings suggest that PCIF1 suppresses CD8+ T cell activation and targeting PCIF1 as a promising strategy to boost anti-tumor immunity.

ORGANISM(S): Mus musculus

PROVIDER: GSE254597 | GEO | 2024/11/14

REPOSITORIES: GEO

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