Immunotherapy in locally advanced head and neck squamous cell carcinoma: The current status and future outlook

Head and neck squamous cell carcinoma presents a significant global health burden, with the majority of cases diagnosed at a locally advanced stage requiring multimodal therapy. While the immune checkpoint inhibitors have transformed outcomes in the recurrent/metastatic setting, their role in locally advanced head and neck squamous cell carcinoma is still evolving. In resectable disease, two recent phase III trials (KEYNOTE-689 and NIVOPOSTOP) have demonstrated meaningful improvements in event-free and disease-free survival, supporting the integration of perioperative and adjuvant immunotherapy into curative strategies. However, the data on the efficacy of immune checkpoint inhibitors in unresectable locally advanced head and neck squamous cell carcinoma remains inconsistent, underscoring the need for more precise patient selection and biomarker-driven approaches. Therapeutic strategies optimized for the timing and sequencing of immune checkpoint inhibitors in accordance with tumor microenvironment dynamics may improve clinical outcomes. Additionally, emerging immunotherapeutics, such as bispecific antibodies, oncolytic viruses, and chimeric antigen receptor T cell therapies, represents a promising frontier in the management of locally advanced head and neck squamous cell carcinoma. Considering the recent advances of the field, we aimed to synthesize current evidence and explore future directions for immunotherapy in locally advanced head and neck squamous cell carcinoma.