Emerging role of immune checkpoint inhibitors in recurrent and metastatic head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) remains a significant public health burden, especially in India, where a majority present with advanced disease and poor prognosis. Recent advances in immunotherapy, particularly immune checkpoint inhibitors (ICIs), have transformed the treatment landscape for recurrent/metastatic HNSCC. This comprehensive review outlines the immunobiological mechanisms underlying HNSCC, including tumor-induced immune evasion through the tumor microenvironment and checkpoint pathways such as programmed cell death protein-1/programmed death-ligand 1, cytotoxic T lymphocyte antigen-4, lymphocyte activation gene-3, T-cell immunoglobulin mucin-3, and T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif. Key clinical trials have established pembrolizumab and nivolumab as effective ICIs, offering superior survival and tolerability over traditional chemotherapy in both first- and second-line settings. Beyond ICIs, the article explores novel approaches including human papillomavirus-targeted vaccines, chimeric antigen receptor T-cell therapies, and combination regimens with epidermal growth factor receptor inhibitors or tyrosine kinase inhibitors. Despite these advancements, therapeutic resistance, immune-related adverse events, and financial toxicity remain key challenges. Future directions emphasize personalized immunotherapy guided by biomarkers and multiomic profiling, along with strategies such as low-dose ICI and bispecific antibodies. Immunotherapy is redefining the prognosis of advanced HNSCC, moving toward long-term disease control and potential chronic management.