LAUSR

Epigenetic factors play important roles in tumor immunology. Histone-lysine N-methyltransferase 2 (KMT2) family genes exert histone H3 methylation, but its role in immunotherapy remains unclear. Our study is the first to investigate the correlation between KMT2 gene mutations and the clinical benefit of immune checkpoint inhibitors (ICI) treatment. We firstly collected a primary ICI-treated cohort ( n  = 546) and found that patients with KMT2A/C mutations yielded better prognosis in terms of progression-free survival (PFS, Hazard ratio [HR] = 0.66, P  = 0.002), objective response rate (ORR, 40.9% vs 20.3%, P  < 0.001), durable clinical benefit (DCB, 48.3% vs 29.8%, P  = 0.001) and overall survival (OS, HR = 0.70, P  = 0.033). Furthermore, we validated the predictive potential of KMT2A/C mutations in an expanded ICI-treated cohort ( n  = 1395). KMT2A/C-mutant patients achieved better OS compared with KMT2A/C-wildtype patients (HR = 0.68, P  = 0.003); and the survival advantages appeared in the majority of cancer subtypes. Our study suggests that KMT2A/C mutations function as a novel and potential predictive biomarker for ICI treatment in multiple solid tumors and the underlying mechanism is worth investigating.