In the training cohort, 33.8% (51/151) melanoma patients harbored GRIN2A mutation. GRIN2A mutation is associated with higher TMB (p<0.001) and higher TNB (p<0.001). Survival analysis demonstrated that GRIN2A mutation resulted in significantly longer PFS (5.6 vs 3.3months; HR, 0.58; p=0.027) and longer OS (22.5 vs 12.8 months; HR, 0.61; p=0.039) in melanoma patients treated with ICIs. While validation cohort1 showed that 22.7% (25/110) melanoma patients harbored GRIN2A mutation and GRIN2A mutation resulted in an increasing trend on TMB with strongly significant difference (p<0.001) and significantly longer OS (22.5 vs 8.3months; HR, 0.53; p=0.025).This study shows that GRIN2A mutation is correlated with higher TMB and TNB in melanoma and serve as a predictive biomarker of ICI benefit in melanoma.