Breaking barriers: epithelial–mesenchymal transition role in melanoma invasion and resistance

Abstract

As a highly aggressive skin cancer, melanoma presents substantial clinical challenges stemming from its metastatic potential and therapy resistance, primarily driven by epithelial–mesenchymal transition (EMT). This review examines EMT’s central role in melanoma progression. Molecular mechanisms are detailed, encompassing transcription factors (ZEB1, Snail, Twist), signaling pathways (transforming growth factor beta/Smad, Wnt/β-catenin, phosphatidylinositol 3-kinase/protein kinase B, mitogen-activated protein kinase/extracellular signal-regulated kinase), plus epigenetic and noncoding RNA regulators. Through extracellular matrix remodeling and phenotypic plasticity, EMT potentiates melanoma cell invasion. This facilitation enables key metastatic cascade steps: intravasation and distant colonization. EMT further drives resistance to both targeted therapies (BRAF/MEK inhibitors) and immunotherapies. Mechanisms include T-cell exclusion, PD-L1 upregulation, and immunosuppressive tumor microenvironment remodeling. Tumor progression is amplified via EMT interactions with stromal components, including cancer-associated fibroblasts and immune cells. Prognostically valuable biomarkers are emerging, particularly EMT gene signatures detectable in circulating tumor cells and tissue samples. Preclinical studies suggest therapeutic potential for strategies targeting EMT transcription factors, signaling pathways, and combination approaches. Despite progress, limitations endure: EMT heterogeneity and inadequate preclinical models. Future work will leverage single-cell analysis and spatial transcriptomics to decipher EMT dynamics. Such advances could enable personalized melanoma treatments. EMTs’ multifaceted role is underscored herein, along with the urgent requirement for innovative therapeutics to enhance patient outcomes.