Cisplatin resistance in oral squamous cell carcinoma: mechanisms, reversal strategies, and emerging technologies

Cisplatin remains a first-line chemotherapeutic agent in the treatment of oral squamous cell carcinoma (OSCC). However, the efficacy of cisplatin is frequently compromised by the development of drug resistance. This review systematically examines the multidimensional mechanisms underlying cisplatin resistance in OSCC and the corresponding strategies to overcome this resistance. Mechanisms of chemoresistance involve complex, multi-layered molecular networks, encompassing dysregulation of key gene expression and signaling pathways, epigenetic remodeling, metabolic reprogramming, evasion of regulated cell death, acquisition of epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) properties, as well as the formation of an immunosuppressive tumor microenvironment (TME). In response to these challenges, multimodal combinatorial approaches are being developed, including small-molecule inhibitors targeting specific resistance nodes, nanotechnology-based targeted drug delivery systems, combination therapies with immune checkpoint inhibitors, and interventions targeting metabolic vulnerabilities. Furthermore, emerging technologies are enabling more precise strategies: patient-derived organoids provide a platform for individualized drug sensitivity testing; single-cell sequencing allows for dissection of cellular heterogeneity within resistant populations and the interactions of these populations with the microenvironment; and artificial intelligence (AI) aids in predictive model building and drug discovery by integrating multi-omics data. In summary, a comprehensive understanding of the systems biology of cisplatin resistance, integrated with novel research paradigms such as nanotechnology, immunotherapy, metabolic targeting, organoid models, single-cell technologies, and AI, will be pivotal for developing personalized combination therapies to ultimately overcome cisplatin resistance in OSCC.