In the training cohort, 10.9% (12/110) melanoma patients harbored USP6 mutation. USP6 mutation is associated with higher TMB (p=0.0007) and results in significantly longer OS (21.3 vs 8.1 months; HR, 0.44; p=0.049).Meanwhile, the validation cohort shows that USP6 mutation results in higher TMB without significant difference (p=0.08) and significantly longer OS (31.5 vs 14.4 months; HR, 0.14; p=0.0026).Furthermore, the correlation analysis between immune infiltration and USP6 mutation status in melanoma shows that both M1 macrophages and follicular helper T cells increased significantly (p=0.02, p=0.033), while differential neutrophil decreased significantly (p=0.048). This study shows that USP6 mutation may serve as a potential positive biomarker of ICIs in melanoma since it correlated with higher TMB, the up regulation of M1 macrophages, follicular helper T cells and the down regulation of differential neutrophil.