Immunotherapy in the Treatment of Head and Neck Squamous Cell Carcinoma: A Review of Current Evidence, Emerging Strategies and Future Directions

Introduction: Head and neck squamous cell carcinomas (HNSCCs) are among the most common cancers worldwide and continue to carry substantial morbidity and mortality despite advances in surgery, radiation therapy (RT), and systemic therapy. Treatment varies according to disease stage, clinical setting, and prior therapy. The immunologically active tumor microenvironment of HNSCC and expression of immune-regulatory pathways have made immunotherapy an important area of therapeutic development. Methods: This is a narrative review of the established and emerging immunotherapeutic strategies for HNSCC, their clinical applications, mechanisms of resistance, and future directions. We used relevant search terms in PubMed to examine the available literature. Discussion and Conclusions: We discuss several immunotherapeutic agents, including PD-1, PD-L1 and CTLA-4 inhibitors, as well as emerging immune checkpoint targets such as LAG-3, TIGIT, TIM-3 and VISTA. We also consider the importance of HPV status in prognosis and treatment response. The role of immunotherapy is considered across disease stages and treatment settings, with particular emphasis on recurrent or metastatic HNSCC and locally advanced HNSCC in the perioperative setting, for which PD-1 inhibitors have demonstrated the clearest clinical benefit and have become an important component of standard therapy. We also review the expanding role of neoadjuvant and adjuvant immunotherapy, as well as combinations with RT, for which efficacy remains under investigation or has been inconsistent across clinical trials. In addition, we examine mechanisms of primary and acquired resistance related to tumor biology and molecular mutations. Finally, we highlight emerging therapeutic approaches, including chimeric antigen receptor T-cell therapy, therapeutic cancer vaccines, and combinations of immunotherapy with proton beam therapy. Together, these developments illustrate the rapidly expanding role of immunotherapy across HNSCC treatment and identify areas in which further investigation may expand therapeutic options and improve outcomes.