Sequencing immunotherapy in locally advanced head and neck squamous cell carcinoma: a narrative clinical-translational review.

Background: Immune checkpoint inhibitors have entered curative-intent treatment of locally advanced head and neck squamous cell carcinoma, but randomized trials have shown divergent results across definitive, perioperative, and postoperative settings. Methods: We reviewed pivotal randomized phase II-III trials and key translational studies to examine how treatment sequence relative to radiation and surgery, together with anatomic context, influences efficacy. Results: Concurrent immunotherapy with definitive chemoradiotherapy has repeatedly failed to improve primary endpoints or locoregional control, a pattern consistent with a myeloid-rich "macrophage sink" model in bulky irradiated tumors. By contrast, perioperative therapy reduced distant failure, consistent with a model of immune priming in intact tumor-draining lymph nodes, whereas postoperative therapy improved locoregional control after removal of gross disease in a "clean bed" of microscopic residual disease. Delayed maintenance after definitive therapy did not demonstrate benefit. HPV status, PD-L1 expression, tumor volume, elective nodal irradiation, and primary subsite may further modulate benefit and contribute to subgroup heterogeneity. Conclusions: In locally advanced head and neck squamous cell carcinoma, immunotherapy benefit appears sequence- and context-dependent. Neoadjuvant treatment may preferentially reduce distant risk, postoperative intensification may reinforce local control in selected high-risk patients, and routine concurrent use with definitive chemoradiotherapy should remain investigational.