The Interplay Between Hyperglycaemia-Induced Metabolic Stress and the EMT-Driven Therapeutic Resistance in Cancer

The phenotypic plasticity of epithelial cells along the epithelial-mesenchymal (E-M) axis, or epithelial-mesenchymal transition (EMT), is a critical aspect of tumour progression and therapeutic resistance. During EMT, epithelial cells gradually acquire mesenchymal traits, facilitating vital functions in embryogenesis, wound healing, fibrosis, and tumour metastasis. This review article investigates the interplay between hyperglycaemia-induced metabolic stress and EMT in the context of therapeutic resistance. The study examines a complex, multifaceted network of molecular mechanisms regulating EMT, including specialised transcription factors and signalling pathways as well as growth factors, integrins, and matrix metalloproteinases in various epithelial carcinomas. Emerging findings have demonstrated the existence of EMT hybrid states along the continuum, possessing heightened metastatic potential and distinctive metabolic signatures that play critical roles in the development of therapeutic resistance in cancer cells. Hyperglycaemia has been particularly highlighted for its potential to promote EMT-driven therapeutic resistance through various interconnected mechanisms. Elevated glucose levels induce the increased production of reactive oxygen species (ROS), activation of EMT-promoting transcription factors, and a metabolic shift towards glycolysis. This hyperglycaemic stress involves upregulation of glucose transporters and glycolytic enzymes creating feed-forward loops that support drug efflux mechanisms and help maintain the mesenchymal phenotype. Clinical data also indicate that hyperglycaemia in OSCC patients is associated with more advanced tumour stages, more ex-tended hospital stays, less effective treatments, and higher rates of local recurrence and distant metastasis. Overall, these insights emphasise the urgent need for a more comprehensive understanding of the underlying mechanisms linking hyperglycaemia and EMT to the treatment resistance axis and to explore glucose control strategies that can be incorporated into cancer treatments to overcome anti-cancer therapy resistance effectively.