Head and Neck Cancer Immunotherapy: Overcoming Limitations and Enhancing Efficacy

ABSTRACT Head and neck cancers (HNCs) are a heterogeneous group of malignancies, including head and neck squamous cell carcinoma (HNSCC), thyroid carcinoma, and salivary gland carcinoma. Despite multidisciplinary treatment approaches, outcomes for advanced HNCs remain poor. Among these, HNSCC has been the most extensively studied in the field of immunotherapy. Immune checkpoint inhibitors (ICIs), particularly anti‐PD‐1 antibodies, have demonstrated survival benefits in R/M HNSCC, but response rates remain modest at 15%–20%, highlighting the need for more effective strategies. Recent advances include the use of neoadjuvant and adjuvant immunotherapy in locally advanced HNSCC, which may improve pathological response rates and long‐term survival. Additionally, novel immunotherapeutic approaches such as tumor antigen‐targeted cancer vaccines and T‐cell receptor‐engineered T‐cell (TCR‐T) therapy are emerging. These strategies aim to enhance tumor‐specific immunity, especially in tumors lacking targetable driver mutations. The tumor microenvironment (TME) in HNSCC plays a pivotal role in modulating immune response and therapeutic efficacy. Immunomodulatory agents such as HDAC inhibitors, TLR agonists, and VEGF inhibitors have shown promise in enhancing ICI responsiveness by altering the immunosuppressive TME. Moreover, the identification of predictive biomarkers, including PD‐L1 expression, tumor mutational burden, and tertiary lymphoid structures, is crucial for patient selection and response prediction. This review provides a comprehensive overview of the current landscape and future directions of immunotherapy for HNCs, with a particular focus on HNSCC. We highlight ongoing clinical challenges and discuss emerging strategies aimed at overcoming resistance and improving clinical outcomes.