Blocking the m6Am methyltransferase PCIF1 releases STAT1-mediated Th1 immunity to potentiate cancer immunotherapy
TL;DR
It is shown, by genomic deletion of PCIF1 specifically in T cells, that PCIF1 represses STAT1 translation via this important mRNA modification, and thereby preventing T cell activation and enforcing a naïve T cell phenotype.
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. Phosphorylated CTD interaction factor 1(PCIF1) is the sole enzyme catalyzing the post-transcriptional N6-methyladenosine(m6A) modification for mRNA. Here the authors show, by genomic deletion of PCIF1specifically in T cells, that PCIF1 represses STAT1 translation via this important mRNA modification, and thereby preventing T cell activation and enforcing a naïve T cell phenotype.