MITF-Driven melanoma plasticity as a core mechanism of therapy resistance: integrating microenvironmental signaling, mechanotransduction, and metabolic reprogramming

Melanoma remains one of the most aggressive cancers, and although immune checkpoint blockade and MAPK-targeted therapies have transformed clinical management, durable responses occur in only a subset of patients. Converging evidence identifies microphthalmia-associated transcription factor (MITF) - dependent phenotype switching as a central, non-genetic mechanism enabling melanoma cells to escape therapy. Dynamic fluctuations in MITF activity permit transitions between differentiated, proliferative states and invasive, drug-resistant phenotypes. This review synthesizes emerging insights into the tumor microenvironmental, mechanical, and metabolic cues that regulate MITF states. These include cytokine-driven inflammatory signaling, hypoxia, cancer-associated fibroblasts, extracellular matrix remodeling, integrin - YAP/TAZ - mediated mechanotransduction, and metabolic reprogramming involving glycolysis - OXPHOS switching, lipid-regulated MITF control, and nutrient-stress responses. By integrating these pathways, MITF-dependent plasticity shapes melanoma adaptation and persistence under therapeutic pressure. Understanding this interconnected network provides a foundation for developing strategies to target phenotype switching and overcome treatment resistance.