Checkpoint inhibitors in squamous cell carcinoma of the head and neck: History and new perspectives.

This review aims to comprehensively examine the historical development, molecular mechanisms and clinical applications of checkpoint inhibitors in squamous cell carcinoma of the head and neck (SCCHN). Squamous cell carcinoma of the head and neck represents a significant global health challenge as the 7th most common malignancy worldwide. Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 and CTLA-4 pathways have emerged as promising therapeutic approaches. Current evidence supports the use of ICIs in the recurrent/metastatic (R/M) setting, while data for neoadjuvant and adjuvant applications is evolving. Pembrolizumab monotherapy or in combination with chemotherapy has demonstrated survival benefits in PD-L1-positive R/M SCCHN, while nivolumab has shown efficacy in the second-line setting. Results from trials combining ICIs with radiotherapy have been mixed, with several phase III studies failing to meet primary endpoints.The integration of ICIs has transformed the treatment landscape for R/M SCCHN, while the ongoing research continues to define their optimal use in earlier disease settings and in novel therapeutic combinations. Future directions include exploring combination strategies with targeted therapies, identifying predictive biomarkers beyond PD-L1 expression, and developing immunotherapy approaches tailored to HPV-positive vs. HPV-negative disease.