The critical role of epithelial-mesenchymal transition (EMT) in colorectal cancer progression and therapeutic outcomes.

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, driven largely by metastatic progression and therapeutic resistance. Despite advances in early detection and systemic treatment, a substantial proportion of patients develop disease that is refractory to conventional therapies. Epithelial-mesenchymal transition (EMT) is a dynamic and reversible cellular program that critically shapes CRC progression. Rather than functioning as a binary switch, EMT in CRC is increasingly understood as epithelial-mesenchymal plasticity (EMP), in which tumor cells occupy partial or hybrid epithelial/mesenchymal states. These intermediate phenotypes retain epithelial features while activating mesenchymal programs, enabling collective invasion, stem-like behavior, immune evasion, and resistance to therapy. This review provides a comprehensive analysis of the molecular drivers of EMT and EMP in CRC, including EMT-associated transcription factors (e.g., SNAIL, ZEB1), key signaling pathways (e.g., TGF-β, Wnt/β-catenin, Notch), and epigenetic regulators such as DNA methylation, histone modifications, and noncoding RNAs. The role of the tumor microenvironment, particularly cancer-associated fibroblasts and tumor-associated macrophages, in stabilizing hybrid EMT states through paracrine signaling and metabolic crosstalk is examined in detail. Importantly, EMP and hybrid EMT states are highlighted as central contributors to resistance across chemotherapy, targeted therapy, radiotherapy, and immunotherapy, driven by phenotypic flexibility rather than irreversible mesenchymal conversion. Emerging therapeutic strategies targeting EMT-associated signaling, epigenetic plasticity, and EMT-immune interactions are discussed, alongside the potential of liquid biopsy approaches to dynamically monitor EMT states during treatment. A refined understanding of epithelial-mesenchymal plasticity and hybrid EMT states is essential for the development of rational combination therapies and biomarker-guided strategies aimed at overcoming therapeutic resistance and limiting metastatic progression in colorectal cancer.