Biological Mechanisms Driving Chemoresistance in Oral Squamous Cell Carcinoma (OSCC): A Review

Drug resistance continues to be a major barrier to the successful treatment of Oral Squamous Cell Carcinoma (OSCC). Numerous processes, including the upregulation of efflux transporters, alterations in drug metabolism, activation of survival pathways like PI3K/Akt, NF-κB, and Wnt/β-catenin, and the Epithelial-Mesenchymal Transition (EMT), are responsible for chemoresistance. By maintaining tumour heterogeneity and self-renewal, Cancer Stem Cells (CSCs) further foster resistance. Among these, activation of pro-survival signaling and CSC-mediated resistance appear most critical. Current research focuses on overcoming these mechanisms through nanocarrier-based drug delivery, gene silencing, autophagy modulation, and targeted inhibition of resistance pathways. Immunotherapeutic approaches, including CAR-T cell therapy combined with checkpoint inhibitors, show encouraging potential. A better understanding of these dominant resistance mechanisms and evidence-based therapeutic strategies is essential to improve clinical medical outcomes in OSCC.