Oral Squamous Cell Carcinoma: A New Era in Molecular Mechanisms and Emerging Targeted Therapies

Oral squamous cell carcinoma (OSCC), the most common oral cancer, presents a clinical challenge due to its complex tumor microenvironment (TME), dysregulated pathways, and poor prognosis. Current methods of diagnosing OSCC use liquid biopsy technologies (ctDNA/microRNAs/exosomes) instead of relying solely on traditional methods such as open surgical biopsy. Liquid biopsy technologies provide non-invasive ways to detect and monitor OSCC in early stages, compared with traditional open surgical biopsy methods. Treatment of OSCC currently relies on chemotherapeutics (cisplatin/5-FU), radiotherapy, and targeted agents (cetuximab). However, resistance is acquired due to TME remodelling (tumor microenvironment) and/or due to epithelial-mesenchymal transition (EMT) through processes such as ABC transporter efflux. This review elucidates key molecular mechanisms, including PD-L1-mediated immune evasion, PI3K/AKT/mTOR hyperactivation, EGFR overexpression, and NF-κB-driven inflammation, which promote proliferation, metastasis, and therapy resistance. One area of study involves the use of nanotechnology to convert phytocompounds (medicinal plants) into therapeutic agents by embedding phytocompounds into nanoparticles created using green synthesis techniques. EPR (Enhanced Permeability and Retention), ligand functionalization for OSCC targeting, improved bioavailability, and reduced toxicity are all advantages that the aforementioned systems provide, offering an opportunity to synergistically develop new therapies with chemotherapeutics for overcoming resistance.

While numerous preclinical studies demonstrate that these newly developed therapies show increased efficacy compared with current therapy options, further work is needed in areas such as standardization, scaling, and clinical translation. As such, the importance of developing pathway-informed diagnostic tests and developing therapies that exploit pathway-specific activity with phytocompounds is emphasized. In addition, large-scale studies should be considered to evaluate the effectiveness of a pathway-informed approach in assessing and differentiating OSCC and personalized therapy strategies, to improve OSCC survival outcomes.