Advances in Immunotherapy for Head and Neck Squamous Cell Carcinoma: Focus on PD-1/PD-L1 Blockade and Beyond

Head and neck squamous cell carcinoma (HNSCC) ranks as the seventh most common cancer globally, with etiological subtypes—carcinogen-driven (human papillomavirus [HPV-negative]) and HPV-driven—shaping tumor immunogenicity and treatment responses. This review highlights immunotherapy’s evolution, focusing on PD-1/PD-L1 blockade. HPV-positive tumors feature a “hot” microenvironment with dense tumor-infiltrating lymphocytes (TILs) and PD-L1 upregulation, yielding better immune checkpoint inhibitor (ICI) outcomes. In contrast, HPV-negative cases exhibit a “cold,” immunosuppressive profile with inferior ICI responses. Landmark trials like KEYNOTE-048 and CheckMate 141 established pembrolizumab and nivolumab as standards for recurrent/metastatic HNSCC, improving median OS (overall survival) by 2 to 4 months over the EXTREME regimen (cetuximab plus platinum-based chemotherapy), especially in patients with PD-L1 Combined Positive Score (CPS) ⩾ 1. Combination strategies enhance efficacy through multiple mechanisms: chemotherapy induces immunogenic cell death, radiotherapy elicits abscopal effects, and cetuximab provides additional antitumor activity. In locally advanced disease, the KEYNOTE-689 trial demonstrated superior event-free survival with perioperative pembrolizumab versus placebo (59.7 vs 29.6 months), supporting treatment de-escalation strategies. Management of immune-related adverse events follows established NCCN/SITC guidelines. Emerging therapies, including anti-LAG-3/TIM-3 and oncolytic viruses, target resistance. Future efforts emphasize multiomic biomarkers and equitable access to optimize outcomes in this heterogeneous malignancy.