Laryngeal squamous cell carcinoma: a functional “two-hit” model of papillomavirus–Epstein–Barr virus synergistic carcinogenesis

Smoking, alcohol consumption, and high-risk human papillomavirus (HPV) infection are recognized risk factors for laryngeal squamous cell carcinoma (LSCC); however, approximately 20%-30% of patients lack typical exposure histories. Furthermore, HPV-positive patients exhibit significant prognostic heterogeneity, suggesting the complexity of multifactorial synergistic carcinogenesis. Recent studies have indicated that the unique anatomy and microenvironment of the larynx may mediate synergistic interactions between pathogens such as Epstein-Barr virus (EBV) and HPV. This functional "two-hit" model drives metabolic reprogramming, disrupts immune responses, and promotes immune evasion, thereby potentially fueling the malignant progression of LSCC. However, coexistence patterns and dynamic interaction mechanisms remain unclear. This systematic review of field advances aims to elucidate potential synergistic mechanisms between HPV and EBV, providing theoretical foundations for pathogen-based multitarget diagnostics and clinical treatment strategies to advance the precision prevention and treatment of LSCC.