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

Abstract

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.