On January 6, 2025, a research team led by Professor Jinfang Zhang, Medical Research Institute and Frontier Science Center for lmmunology and Metabolism of Wuhan University, published its latest findings in Nature Immunology, titled “The epitranscriptional factor PCIF1 orchestrates CD8⁺ T cell ferroptosis and activation to govern anti-tumor immunity.”

In this study, researchers found that PCIF1, an RNA N6,2′-O-dimethyladenosine (m⁶Am) methyltransferase, as a negative regulator of CD8⁺ T cell-mediated anti-tumor responses. Whole-body or T cell-specific Pcif1 knockout (KO) significantly suppresses tumor growth in mice. Single-cell RNA sequencing reveals an increased infiltration of cytotoxic CD8⁺ T cells in Pcif1-deficient tumors. Mechanistic studies using proteomics and m⁶Am sequencing show that Pcif1 KO enhances the expression of key m⁶Am-modified targets, including ferroptosis suppressor genes (Fth1, Slc3a2) and the T cell activation gene Cd69, which confer resistance to ferroptosis and promote CD8⁺ T cell activation. Remarkably, Pcif1-deficient mice exhibit improved responses to anti-PD-1 immunotherapy, and Pcif1 KO CAR T cells demonstrate superior tumor control. Clinically, cancer patients with low PCIF1 expression in T cells show enhanced responsiveness to immunotherapies.

These findings establish PCIF1 as a critical suppressor of CD8⁺ T cell activation and a promising therapeutic target to boost anti-tumor immunity.

Full text link: https://www.nature.com/articles/s41590-024-02047-w