Arginine methyltransferase PRMT3 suppresses tumor-intrinsic immunity via promoting cGAS methylation.

Loss or lack tumor immunogenicity promotes immune escape and resistance to immunotherapy. Arginine methylation, a key protein post-translational modification, participates in tumor progression and therapy resistance. However, whether arginine methylation directly influences the tumor immunogenicity and thereby modulates antitumor immune responses remains poorly understood. Here, we report that protein arginine methyltransferase 3 (PRMT3) exhibited a significantly negative association with antitumor immune signatures and survival outcomes in multiple cancers. Tumor-intrinsic PRMT3 deletion markedly delays tumor growth by promoting CD8+ T cell infiltration and functional activation through the modulation of type I interferon (IFN) signaling. Mechanistically, PRMT3 catalyzes arginine asymmetric-dimethylation at the conserved Arg364 residue of cGAS, suppressing its capacity to activate the downstream STING signaling, which ultimately affects the tumor immunogenicity and overall antitumor immune responses. Combining PRMT3 deletion or pharmacological inhibition with anti-PD-1 antibody therapy achieved profoundly synergistic tumor control and elicited tumor-specific immunological memory. Collectively, our findings delineate a critical regulatory role of PRMT3 on tumor-intrinsic cGAS-mediated adaptive immunity, proposing immunogenicity-enhanced cancer treatment as a transformative strategy to achieve potentiated antitumor efficacy.