Consistent with its role, we demonstrate that KMT5C activates the DNA repair response to inhibit the STING‐IRF3 pathway, downstream type I IFN signaling and CCL5 secretion, leading to the downregulation of CD8+ T cell infiltration and function in NSCLC, ultimately facilitating tumor immune evasion and tumor progression. This evidence concerns the gene IRF3 and neoplasm.