Molecular Mechanisms in Oral Squamous Cell Carcinoma: Integrative Roles of Cancer-Associated Fibroblasts, Immune Microenvironment, and Precision Therapeutic Opportunities

Oral squamous cell carcinoma (OSCC) remains a major global health burden due to aggressive invasion, early metastasis, therapeutic resistance, and poor long-term survival. Beyond tumor-intrinsic genetic and epigenetic alterations, accumulating evidence highlights the critical role of the tumor microenvironment in shaping OSCC progression and clinical outcomes. Cancer-associated fibroblasts (CAFs) and immune cells orchestrate tumor initiation, immune evasion, and recurrence through extracellular matrix remodeling, cytokine signaling, angiogenesis, and metabolic and redox regulation. Key oncogenic pathways, including EGFR/PI3K/AKT/mTOR, TGF-β, Wnt, and Notch, integrate with non-coding RNA networks to reinforce stemness, epithelial-mesenchymal transition, and therapy resistance. Moreover, PD-1/PD-L1-mediated immune escape, CAF-driven biomechanical remodeling, and metabolic reprogramming such as aerobic glycolysis and lipid metabolism contribute to OSCC heterogeneity. This review synthesizes current insights into OSCC across genomic, epigenetic, metabolic, and microenvironmental dimensions, emphasizing CAF biology, immune landscape reprogramming, and non-coding RNA regulation. We further discuss emerging biomarkers, liquid biopsy approaches, and targeted therapeutic strategies, providing a system-level framework for biomarker-guided stratification and precision combination therapies in OSCC.