Basic and Clinical Evidence for Perioperative Immunotherapy in Resectable HNSCC

Background: Perioperative immunotherapy has emerged as a promising strategy for improving outcomes in patients with resectable head and neck squamous cell carcinoma (HNSCC). However, its biological rationale, clinical evidence, and optimal implementation remain incompletely defined. Methods: We conducted a narrative review of the current literature, integrating preclinical and clinical evidence on perioperative immune checkpoint inhibitor (ICI) therapy in resectable HNSCC, with particular attention to the immunological impact of surgery, tumor-draining lymph nodes, and treatment sequencing. Results: Neoadjuvant immunotherapy exploits the presence of intact tumor antigen and preserved lymphatic architecture, enabling broad T-cell priming, clonal expansion, and systemic immune memory formation. In contrast, adjuvant immunotherapy primarily targets residual microscopic disease and relies on preexisting tumor-reactive T cells, suggesting that these strategies are biologically distinct. Early-phase clinical trials have demonstrated the safety and feasibility of perioperative ICIs, with evidence of pathological responses. Recent phase III trials, including KEYNOTE-689 and NIVOPOSTOP, have provided practice-relevant evidence supporting the integration of ICIs into perioperative treatment, demonstrating improved event-free survival and clinical outcomes in selected populations. Several challenges remain, including optimal patient selection, lack of validated biomarkers, and treatment sequencing after perioperative ICI exposure. Conclusions: Perioperative immunotherapy represents a promising practice-relevant strategy in resectable HNSCC. Further studies are required to refine patient selection, develop predictive biomarkers, and optimize treatment sequencing to maximize clinical benefit.