Epithelial–Mesenchymal Transition in Cancer: Insights Into Therapeutic Targets and Clinical Implications

Dhasarathdev Srinivasan ¹, Ranjith Balakrishnan ¹, Ankush Chauhan ², Jeevan Kumar ³, Dinesh Murugan Girija ⁴, Reena Shrestha ⁵, Rupendra Shrestha ^6*, Rajasekaran Subbarayan ^1,2*

1. Centre for Advanced Biotherapeutics and Regenerative Medicine, Faculty of Research, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, Tamil Nadu, India

2. Centre for Herbal Pharmacology and Environmental Sustainability, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, Tamil Nadu, India

3. Department of Biomedical Sciences, The Apollo University, Chittoor, Andhra Pradesh, India

4. Vopec Pharmaceuticals Pvt. Limited, Research and Development Division, Chennai, India

5. Department of Internal Medicine, Berkshire Medical Center, Pittsfield, Massachusetts, USA

6. Department of Natural and Applied Sciences, Nexus Institute of Research and Innovation (NIRI), Lalitpur, Nepal, India

Publications: MedComm. 2025;6(9):e70333. doi: 10.1002/mco2.70333 

Abstract – Radiation therapy is a fundamental component of cancer treatment, benefiting 50%–70% of patients by selectively targeting malignant tissues. However, radioresistance remains a significant challenge, often driven by epithelial–mesenchymal transition (EMT). EMT increases cancer invasiveness and metastasis by upregulating mesenchymal markers, including vimentin and N-cadherin, and downregulating epithelial markers, such as E-cadherin. EMT under radiation involves principal signaling pathways, including TGF-β, Wnt/β-catenin, Notch, and ERK, which regulate EMT through transcription factors such as Snail, Slug, Twist, and Zeb1/2. These alterations drive cytoskeletal reorganization, decrease cell–cell adhesion, and enhance extracellular matrix degradation via integrins, MMP-2, and MMP-9. We also explored how growth hormones, inflammatory cytokines, and hypoxia in the tumor microenvironment affect radiation-induced EMT. Targeting EMT pathways with monoclonal antibodies and small-molecule inhibitors of signaling pathways may help overcome radioresistance. However, due to the dual role of EMT in cancer progression and tissue regeneration, precise treatment strategies are essential. There is a lack of comprehensive multi-omics studies that provide insights into postradiation EMT progression. This review examines how radiation induces EMT and its impact on metastasis and immune responses while also proposing therapeutic approaches. Integrating EMT-targeting strategies with existing cancer treatments could enhance the effectiveness of radiotherapy and improve patient outcomes.

Cite: Srinivasan, D., Balakrishnan, R., Chauhan, A., Kumar, J., Girija, D.M., Shrestha, R., Shrestha, R., Subbarayan, R. Epithelial–Mesenchymal Transition in Cancer: Insights Into Therapeutic Targets and Clinical Implications. MedComm. 2025;6(9):e70333.