Oral Squamous Cell Carcinoma: A Comprehensive Review of Risk Factors, Molecular Pathogenesis, and Prevention Strategies

Oral squamous cell carcinoma (OSCC) remains a major contributor to global head and neck cancer morbidity and mortality. This review examines the epidemiological aspects of OSCC and the biological mechanisms through which established exposures (e.g., tobacco, alcohol, betel/areca nut, socioeconomic and selected viral infections etc.) and emerging determinants (oral microbiome dysbiosis, host genetics/epigenetics, and immune dysfunction) converge to initiate and promote malignant transformation. We emphasize that OSCC risk is probabilistic and multifactorial: incidence rises markedly with age and cumulative exposures, yet the majority of individuals risk exposed to these risk factors will not develop disease. Mechanistically, carcinogen-driven DNA damages intersects with dysbiosis characterized by enrichment of periodontal pathobionts (notably Porphyromonas gingivalis and Fusobacterium nucleatum), which can sustain chronic inflammation, increase local generation of acetaldehyde and nitrosamines, and promote immune evasion via expansion of immunosuppressive cell populations and checkpoint signaling. We summarize recurrent molecular and genetic alterations in OSCC and highlight progress in early detection, including adjunctive visualization, optical and vibrational spectroscopy, and liquid-biopsy approaches using salivary and blood-based biomarkers. Finally, we discuss prevention opportunities spanning risk-factor modification, historical cultural practices, oral hygiene to mitigate dysbiosis (pH modulation and probiotics), and dietary/nutritional strategies. Integrating exposure history with microbial and molecular profiling may enable risk-stratified screening and prevention paradigms for OSCC.