Blocking the m⁶Am methyltransferase PCIF1 releases STAT1-mediated Th1 immunity to potentiate cancer immunotherapy.

Abstract

Naïve T cells maintain a delicate balance between quiescence and rapid activation, which involves multiple layers of regulation beyond transcription. Here, we identify the RNA modification N6,2'-O-dimethyladenosine (m⁶Am) and its methyltransferase PCIF1 as critical enforcers of T cell quiescence. During CD4⁺ T cell activation, m⁶Am levels are dynamically downregulated. T-cell-specific PCIF1 knockout (cKO) mice exhibit potent tumor suppression, driven by enhanced Th1 differentiation and subsequent amplification of NK cell cytotoxicity. Mechanistically, PCIF1 represses STAT1 translation via m⁶Am modification of its mRNA, thereby constraining Th1 commitment. Activation-induced PCIF1 downregulation releases this translational brake, enabling rapid Th1 polarization. Crucially, we identify Suramin as a pharmacological PCIF1 inhibitor that disrupts m⁶Am modification, boosts Th1 responses, and suppresses tumor growth. Our findings establish the PCIF1-m⁶Am-STAT1 axis as a translational checkpoint governing T cell differentiation and suggest that targeting PCIF1 represents a potential strategy for tumor immunotherapy.