KMT5A-mediated methylation of IRF3 promotes tumor progression through immune suppression

Lysine methylation is a critical post-translational modification (PTM) involved in diverse physiological and pathological processes. Interferon regulatory factor 3 (IRF3) plays a pivotal role in antitumor immunity; however, the regulatory mechanisms and functional impact of IRF3 methylation within the tumor microenvironment remain incompletely understood. This study demonstrates that monomethylation of IRF3 at lysine 193(K193) suppresses its phosphorylation-dependent activation. Mass spectrometry-based protein interactome analysis identified lysine methyltransferase 5A (KMT5A) as the key enzyme responsible for IRF3 K193 monomethylation. In colorectal cancer (CRC), aberrantly high expression of KMT5A impaired in vivo antitumor immune responses. Mechanistically, KMT5A catalyzes IRF3 monomethylation at K193, which impedes IRF3 phosphorylation and subsequent activation, thereby suppressing the production of type I interferons (IFN-I). Collectively, these findings elucidate KMT5A-mediated IRF3 K193 methylation as a critical regulatory axis promoting tumor immune evasion and progression. Furthermore, IRF3 K193 methylation represents a promising therapeutic target for CRC intervention.