Lactylation-driven molecular taxonomy of melanoma: linking epigenetic modifications to immune evasion and clinical outcomes

Lactylation, a post-translational modification derived from elevated lactate levels, has gained attention as a potential regulator of melanoma's tumor metabolism and immune responses. Here, we combined single-cell RNA sequencing and bulk transcriptome profiling of cutaneous melanoma samples to establish a lactation-centric prognostic model. Our analyses revealed melanocytes as the most acetylation-enriched cell population and identified a six-gene lactylation signature that stratified patients into high- and low-risk groups with distinct survival outcomes. Mechanistically, high-risk tumors demonstrated significant immunosuppressive features characterized by M2 macrophage accumulation and depleted CD8+ T-cell activity, corresponding to reduced sensitivity to certain chemotherapeutic drugs. Pathway enrichment studies implicated DNA repair, Hedgehog, and JAK-STAT signaling in driving the aggressive phenotype of high-acetylation tumors. Additionally, pseudotime trajectory analyses highlighted developmental shifts in gene expression related to lactylation during melanocyte differentiation. The signature demonstrated robust predictive accuracy in training, testing, and external validation cohorts. Functional validation confirmed the critical role of RAN in promoting proliferation and migration in vitro. These findings unveil lactylation as a critical epigenetic factor influencing melanoma progression and immune evasion, offering a novel prognostic framework and potential therapeutic targets for precision medicine.