Epithelial-mesenchymal transition in cancer metastasis: Molecular mechanisms, microenvironmental regulation, and therapeutic targeting

Epithelial-mesenchymal transition is a crucial driver of cancer metastasis, enabling cancer cells to acquire invasive and migratory characteristics. This review synthesizes the molecular mechanisms underlying EMT, focusing on the transcription factors Snail, ZEB, and Twist, as well as the signaling pathways TGF-β/Smad and PI3K/Akt that regulate phenotypic plasticity. Components of the tumor microenvironment, including cytokines, hypoxia, and cancer-associated fibroblasts, synergistically activate EMT through dynamic interactions with oncogenic signaling pathways. The heterogeneity of EMT across different cancer types, such as hormone-mediated regulation in breast cancer and the involvement of non-coding RNAs in gastric malignancies, highlights its context-dependent role. Emerging therapies targeting EMT include small-molecule inhibitors, natural compounds, and herbal formulations, which aim to reverse EMT markers such as E-cadherin loss and vimentin upregulation, thereby sensitizing cancers to chemotherapy. Combinatorial approaches that integrate EMT suppression with conventional treatments show promise in overcoming drug resistance. However, challenges remain in clinical translation due to the plasticity of EMT and the adaptability of cancers. Future efforts should prioritize biomarker-driven strategies, and multi-omics approaches to refine the therapeutic targeting of EMT in metastatic cancers.