Mettl3-catalyzed m6A methylation determines CD8+ T cell differentiation fate in tumor

Abstract

The heterogeneity in patient responses to immune checkpoint blockade (ICB) is dictated by the relative abundance of exhausted CD8 T cell (Tex) subsets with distinct therapeutic responsiveness. Progenitor exhausted (pTex) cells remain sensitive to ICB, whereas terminally exhausted (tTex) cells are refractory; however, the molecular cues that bias differentiation toward these divergent fates remain poorly defined. Here, we identify the RNA methyltransferase Mettl3 as a central regulator of Tex fate. Across murine tumor models, human T cells, and adoptive transfer systems, Mettl3 expression is selectively enriched in tTex cells and inversely correlated with TCF1 pTex populations. Mechanistically, Mettl3 drives terminal exhaustion by stabilizing DNMT3B transcripts via mA modification, enforcing CpG methylation and chromatin compaction at memory-associated loci. Inhibition of the Mettl3-Dnmt3b axis reprograms chromatin accessibility toward memory-like states, thereby preserving progenitor potential and effector function. Consequently, T cells lacking Mettl3-Dnmt3b activity persist longer, mount robust recall responses, and achieve superior tumor control with enhanced responsiveness to PD-1 blockade. These findings establish the Mettl3-mA-Dnmt3b axis as a molecular rheostat of CD8 T cell fate, coupling epitranscriptomic regulation to epigenetic remodeling, and reveal a tractable pathway to improve the durability of cancer immunotherapy.