Early‐Onset Oral Squamous Cell Carcinoma: Emerging Biological Insights, Risk Factors and Clinical Implications

Background: Early-onset oral squamous cell carcinoma (EO-OSCC), commonly defined as occurring in individuals under 50 years of age, is increasingly recognized as a potentially distinct clinical subset with differences in exposure patterns and tumor biology compared with conventional oral squamous cell carcinoma (OSCC). Unlike typical OSCC, which is strongly associated with tobacco and alcohol, EO-OSCC more frequently affects never-smokers/never-drinkers, posing challenges for early recognition, risk stratification, and management. Objective: This review integrates evidence mapping with narrative synthesis to summarize current knowledge on EO-OSCC, focusing on epidemiology, emerging risk factors, molecular alterations, tumor microenvironment characteristics, and clinical implications. Methods: Literature was searched across PubMed, Scopus, Embase, Web of Science, and the Cochrane Library up to August 2025, complemented by global cancer databases (GLOBOCAN/Cancer Tomorrow) and international trial registries. Results: Available data suggest distinct biological features, including relatively low tumor mutational burden, recurrent alterations in CDKN2A, TP53, NOTCH1, and EGFR, epigenetic dysregulation, and a checkpoint-dominant immunosuppressive tumor microenvironment. Alongside traditional carcinogens, modifiable determinants such as sugar-sweetened beverages, electronic cigarette use, and oral microbial dysbiosis have emerged as plausible contributors, although evidence remains heterogeneous. Despite frequently aggressive histopathologic features, younger patients may tolerate intensive multimodal therapies better and achieve favorable outcomes. Conclusion: These findings highlight the urgent need for age-specific prognostic tools, biomarker-guided therapies, and early detection protocols. International collaboration will be key to improving survival and long-term quality of life in this growing patient population.