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RNA N6-methyladenosine (m 6 A) modification in tumorigenesis and progression has been highlighted and discovered in recent years. However, the molecular and clinical implications of m 6 A modification in melanoma tumor microenvironment (TME) and immune infiltration remain largely unknown. Here, we utilized consensus molecular clustering with nonnegative matrix factorization based on the melanoma transcriptomic profiles of 23 m 6 A regulators to determine the m 6 A modification clusters and m 6 A-related gene signature. Three distinct m 6 A modification patterns (m 6 A-C1, C2, and C3), which are characterized by specific m 6 A regulator expression, survival outcomes, and biological pathways, were identified in more than 1,000 melanoma samples. The immune profile analyses showed that these three m 6 A modification subtypes were highly consistent with the three known immune phenotypes: immune-desert (C1), immune-excluded (C2), and immune-inflamed (C3). Tumor digital cytometry (CIBERSORT, ssGSEA) algorithm revealed an upregulated infiltration of CD8 +  T cell and NK cell in m 6 A-C3 subtype. An m 6 A scoring scheme calculated by principal component of m 6 A signatures stratified melanoma patients into high- and low-m 6 sig score subgroups; a high score was significantly associated with prolonged survival and enhanced immune infiltration. Furthermore, fewer somatic copy number alternations (SCNA) and PD-L1 expression were found in patients with high m 6 Sig score. In addition, patients with high m 6 Sig score demonstrated marked immune responses and durable clinical benefits in two independent immunotherapy cohorts. Overall, this study indicated that m 6 A modification is involved in melanoma tumor microenvironment immune regulation and contributes to formation of tumor immunogenicity. Comprehensive evaluation of the m 6 A modification pattern of individual tumors will provide more insights into molecular mechanisms of TME characterization and promote more effective personalized biotherapy strategies.

Identification of m6A Regulator-Associated Methylation Modification Clusters and Immune Profiles in Melanoma