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MITF-Driven melanoma plasticity as a core mechanism of therapy resistance: integrating microenvironmental signaling, mechanotransduction, and metabolic reprogramming
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DOI：10.1080/15384101.2026.2684937.png)
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Abstract
En 中文
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.
Keywords:
MITF
melanoma
phenotype switching
therapy resistance
tumor microenvironment
mechanotransduction
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