HPV-positive head and neck squamous cell carcinoma: From molecular pathogenesis to therapeutic frontiers.

The global incidence of human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC) has increased markedly over recent decades, leading to a fundamental shift in the epidemiology and clinical management of head and neck malignancies. HPV-positive HNSCC represents a biologically and clinically distinct disease entity, characterized by unique molecular features, improved treatment responsiveness, and a more favorable prognosis compared with HPV-negative tumors. However, the optimal integration of molecular insights with evolving therapeutic strategies remains an ongoing clinical and translational challenge. In this review, we summarize the etiological role of HPV in the pathogenesis of HNSCC and delineate key differences in epidemiology, molecular biology, and clinical presentation between HPV-positive and HPV-negative disease. We further examine current standard-of-care treatments, including surgery, radiotherapy, and chemotherapy, with particular emphasis on de-escalation strategies aimed at reducing long-term toxicity while maintaining oncologic efficacy in HPV-positive patients. Emerging immunotherapeutic approaches have demonstrated encouraging activity in recurrent or metastatic disease. Moreover, therapeutic vaccine development, including DNA-, mRNA-, peptide-, and viral vector-based platforms targeting HPV E6/E7 oncoproteins, represents a rapidly evolving area with the potential to enhance antitumor immunity. This review also highlights ongoing clinical trials that may reshape the future landscape of treatment for HPV-positive HNSCC. Collectively, these advances emphasize the importance of HPV status in guiding personalized management strategies and improving patient outcomes.