Prasanna Srinivasan Ramalingam, Baby Ilma, Md Sadique Hussain, Vikash Jakhmola, Rabab Fatima, Amita Joshi Rana, Mohit Agrawal, Sumel Ashique, Janaki Ramaiah Mekala, Sivakumar Arumugam
The epithelial-mesenchymal transition (EMT) is a central plasticity program in cancer. It enables carcinoma cells to acquire migratory, invasive, immunomodulatory, and therapy-resistant phenotypes. As a result, EMT is a key driver of metastatic progression and poor prognosis. This overview summarizes recent mechanistic innovations across EMT-inducing transcription factors (SNAIL, SLUG, TWIST, ZEB) and their interactions with major signaling cascades, including TGF-β/SMAD, Wnt/β-catenin, Notch, PI3K/AKT/mTOR, and Hippo (YAP/TAZ). Together, these cascades integrate cues from the TME to sustain partial/hybrid EMT states and maintain cancer stemness. We present a review of epigenetic and post-transcriptional regulation of EMT (DNA methylation, histone regulation, and non-coding RNAs) and their role in reversible states transitions and drug tolerance. The translational section highlights advance in biomarker development and limitations of the static, single-timepoint assays in capturing EMT dynamics. We describe the possibilities of longitudinal, multimodal assessment, such as liquid biopsy, spatial profiling, and integrative multi-omics, for real-time monitoring of EMT states. Moreover, we explore the therapeutic opportunities involving epigenetic regulators, RNA-based interventions, EMT-immune crosstalk target, and selected natural products that modulate EMT circuits. Lastly, we propose a precision-oncology model that can consolidate the use of EMT-state stratification (epithelial-predominant, hybrid-mesenchymal, mesenchymal-predominant), adaptive monitoring, and rational combination therapies (with immunotherapy, ferroptosis inducers, and targeted agents) to overcome metastasis and resistance. Taken together, positioning EMT as a continuous, druggable spectrum, over binary switch, allows patient stratification using biomarkers and supports the development of next-generation interventions to reduce the risk of metastasis and enhance long-term clinical outcomes.