Salvianolic acid B inhibits melanoma via dual modulation of glycolysis and NK/T cell immunity.

Melanoma is a highly aggressive malignancy, and resistance to immune checkpoint inhibitors (ICIs) remains particularly pronounced in acral and mucosal subtypes among Chinese patients. A key driver of this resistance is glycolysis-driven lactate accumulation, which fosters an immunosuppressive tumor microenvironment (TME). Salvianolic acid B (Sal B), a natural compound derived from Salvia miltiorrhiza, has shown therapeutic promise, but its anti-melanoma mechanism remains largely undefined. Here, we used network pharmacology to predict the potential core targets of Sal B in melanoma, and validated the antitumor effect of Sal B in A375 cells and xenograft mouse models. Sal B markedly inhibited cell proliferation, migration, and invasion, induced G2/M cell cycle arrest and apoptosis, and suppressed glycolytic activity. In vivo, Sal B significantly reduced tumor growth, and transcriptomic profiling revealed upregulation of immune-related genes, including those in the TNF pathway. Consistently, Sal B treatment increased the proportions of NK and CD8 T cells, indicating that it may reshape the TME through metabolic reprogramming and immune activation. Compared to single-agent ICIs, Sal B offers dual metabolic-immune modulation, providing a new avenue for integrative immunotherapy in refractory melanoma prevalent in Chinese patients. Its natural origin and multi-target features may further reduce toxicity and enhance therapeutic precision, supporting the development of personalized treatment strategies.