Perioperative immune checkpoint inhibition in head and neck squamous cell carcinoma: a 10-year review

Immune checkpoint blockade has transformed management of recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), yet efforts to integrate immunotherapy into curative chemoradiation have failed to improve outcomes. We conducted a narrative review of English-language literature published between 2015 and 2025, searching PubMed/MEDLINE, Embase, Web of Science, and ClinicalTrials.gov for perioperative (neoadjuvant and/or adjuvant) immunotherapy studies in resectable HNSCC, and reviewed translational and cross-tumor neoadjuvant data relevant to perioperative trial design. Across early-phase and randomized perioperative trials, neoadjuvant programmed cell death 1 (PD-1)-based strategies were consistently feasible and induced pathologic tumor regression in a subset of patients. Protocol-defined, treatment-related surgical delays were uncommon; however, delays overall were more frequent with perioperative pembrolizumab in the phase III setting (38 vs. 10 participants in KEYNOTE-689; median time to surgery 3.0 vs. 1.9 weeks), so preserved surgical deliverability should not be equated with absence of scheduling impact. Phase II studies associated depth of pathologic response and immune-inflamed tumor features with improved disease-free outcomes. These findings informed phase III perioperative trials, culminating in KEYNOTE-689, which improved event-free survival without compromising surgical completion. In contrast, phase III trials evaluating concurrent PD-1/programmed death-ligand 1 (PD-L1) checkpoint blockade with definitive chemoradiotherapy showed no meaningful survival benefit. Collectively, current evidence supports perioperative pembrolizumab added to surgery and risk-adapted adjuvant therapy in selected patients with resectable locally advanced HNSCC, while other perioperative immune checkpoint inhibitor regimens remain investigational. This conclusion rests principally on a single positive phase III trial (KEYNOTE-689), and the June 2025 FDA approval is restricted to tumors with a PD-L1 combined positive score (CPS) of at least 1. The relative contributions of neoadjuvant priming, concurrent postoperative therapy, and prolonged adjuvant maintenance cannot be disentangled within the KEYNOTE-689 design, and no perioperative schedule can yet be designated optimal. Ongoing studies will refine biomarker-guided selection, sequencing, and duration.