{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T12:18:56Z","timestamp":1788437936449,"version":"build-2803163510"},"reference-count":27,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We reviewed pivotal randomized phase II\u2013III trials and key translational studies to examine how treatment sequence relative to radiation and surgery, together with anatomic context, influences efficacy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Concurrent immunotherapy with definitive chemoradiotherapy has repeatedly failed to improve primary endpoints or locoregional control, a pattern consistent with a myeloid-rich \u201cmacrophage sink\u201d 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 \u201cclean bed\u201d 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1895540","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T12:03:21Z","timestamp":1788437001000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Sequencing immunotherapy in locally advanced head and neck squamous cell carcinoma: a narrative clinical-translational review"],"prefix":"10.3389","volume":"16","author":[{"given":"Ruey-Long","family":"Hong","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, National Taiwan University Cancer Center","place":["Taipei, Taiwan"]},{"name":"Department of Oncology, National Taiwan University 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