Epithelial–Mesenchymal Plasticity in Cancer: Transcriptional Regulation, Biomarker Challenges, and Emerging Therapeutic Opportunities

Abstract

Epithelial–mesenchymal transition (EMT) is increasingly recognized as a dynamic process of epithelial–mesenchymal plasticity (EMP) rather than a binary switch between epithelial and mesenchymal phenotypes. This plasticity enables tumor cells to acquire invasive, metastatic, stem-like, and therapy-resistant characteristics that contribute to cancer progression and poor clinical outcomes. Despite extensive investigation, significant challenges remain in understanding the functional significance of partial EMT states, identifying robust biomarkers that capture EMT heterogeneity, and translating EMT-targeted interventions into clinical practice. This review critically examines the molecular mechanisms governing EMT, including transcriptional regulators, signaling pathways, epigenetic modifications, and tumor microenvironmental influences. Particular emphasis is placed on hybrid epithelial/mesenchymal states, which have emerged as key drivers of metastatic fitness and therapeutic resistance. We further evaluate established and emerging EMT biomarkers, including E-cadherin, N-cadherin, vimentin, circulating tumor cells, and exosome-derived signatures, highlighting their opportunities and limitations in clinical applications. Finally, we discuss current therapeutic strategies targeting EMT-associated pathways and explain why many promising preclinical approaches have faced translational barriers. By integrating mechanistic, biomarker, and therapeutic perspectives, this review proposes that understanding and targeting epithelial–mesenchymal plasticity, rather than EMT alone, may provide a more effective framework for precision oncology and metastasis prevention.