Immune Checkpoint Inhibitors in Resectable and Locoregionally Advanced HNSCC: Past Lessons, Present Evidence, and Future Directions.

The integration of ICIs has reshaped therapeutic strategies in head and neck squamous cell carcinoma (HNSCC). ICIs are established in recurrent/metastatic (R/M) HNSCC and have been extensively evaluated in resectable and locoregionally advanced (LA) disease, without success until the recent KEYNOTE-689 and NIVOPOSTOP studies. These pivotal trials demonstrate that perioperative and adjuvant ICIs can improve clinical outcomes and change clinical practice. Their implementation in resectable HNSCC may raise several unanswered questions, including optimal sequencing with surgery and radiotherapy, patient selection, and management of patients who progress to R/M disease after (neo)adjuvant therapy. This review summarizes the most recent evidence on ICIs in LA-HNSCC, highlighting both successes and challenges in clinical development, clinical practice implications, unresolved questions, and emerging strategies. We provide an overview of ongoing studies exploring ICI-based approaches and combinations for neoadjuvant adaptive response, surgical strategies including surgical conversion and organ preservation, and radiotherapy optimization. Additionally, we review ongoing clinical trials evaluating ICIs in combination with chemotherapy, antibody-drug conjugates, targeted therapy, radiotherapy-including stereotactic body radiotherapy (SBRT), novel ICIs, and therapeutic cancer vaccines targeting HPV or tumor neoantigens.