Immuno-oncology in the perioperative setting: the next frontier in resectable head and neck cancers – a systematic review

Perioperative immunotherapy-particularly immune checkpoint inhibitors (ICIs)-has emerged as a promising strategy to reduce recurrence in resectable head and neck squamous cell carcinoma (HNSCC). Despite standard multimodal therapy, nearly half of patients experience relapse within five years. ICIs such as nivolumab and pembrolizumab have transformed recurrent/metastatic HNSCC, and their integration into curative settings is under active investigation.We conducted a PRISMA-compliant systematic review of PubMed, Embase, Cochrane Library, and major oncology conference proceedings (2018-2026) to identify clinical trials evaluating ICIs in the perioperative setting of HNSCC. Two reviewers independently screened and extracted data. Outcomes of interest included safety, pathological response, event-free or disease-free survival (EFS/DFS), and overall survival (OS). Meta-analysis was not performed due to heterogeneous study designs.Twenty-five studies (18 published, 7 conference abstracts) met inclusion criteria. Neoadjuvant ICI monotherapy was safe but showed modest major pathological response (MPR) rates (~ 6%). Combination strategies were more effective: the IMCISION trial reported 35% MPR with nivolumab plus ipilimumab vs. 17% with nivolumab alone. Neoadjuvant therapy did not delay surgery. In the adjuvant setting, the NIVOPOSTOP trial showed improved 3-year DFS with nivolumab plus postoperative chemoradiotherapy (63.1% vs. 52.5%). The KEYNOTE-689 trial showed perioperative pembrolizumab significantly improved EFS (51.8 vs. 30.4 months), leading to FDA approval in PD-L1 CPS ≥ 1 tumors.Pathologic response correlated with improved survival. Ongoing trials are refining biomarkers, combinations, and sequencing. Perioperative immunotherapy is reshaping curative-intent management of HNSCC, establishing a new multidisciplinary treatment paradigm.