{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T06:11:26Z","timestamp":1784268686058,"version":"3.55.0"},"reference-count":90,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T00:00:00Z","timestamp":1784246400000},"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. Immunol."],"abstract":"<jats:p>\n                    In the era of immunotherapy, head and neck squamous cell carcinoma (HNSCC) has demonstrated clear benefits from immune-based treatments and is widely regarded as a tumor type with high immunotherapeutic potential. These tumors are characterized by robust and persistent inflammatory responses that actively drive tumor initiation and progression while concurrently shaping their sensitivity or resistance to therapy. Inflammation simultaneously creates therapeutic vulnerabilities and barriers by altering tumor behavior and reprogramming the immune microenvironment. This review examined HNSCC through a tripartite prism of inflammation, immunity, and tumor biology to demonstrate how chronic inflammatory cues rewire immune cells, reshape signaling circuits, and remodel tissue architecture, ultimately altering responses to immunotherapy. We first examined how immune cell reprogramming occurs under inflammatory pressure. Macrophages, regulatory T cells, exhausted CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells, and specialized dendritic cell subsets can switch roles\u2014from tumor-clearing sentinels to promoters of tumor growth, stemness, and invasion. This plasticity\u2014sometimes transient, sometimes entrenched\u2014determines whether the immune ecosystem favors elimination or tolerance, and consequently whether immune checkpoint blockade succeeds or fails. Next, we catalogued the inflammation-linked pathways and readouts that capture these state changes. Signaling hubs such as NF-\u03baB\/STAT3, IL-6\/TNF\u03b1, TGF-\u03b2, HA-CD44, and PI3K-4EBP1-SOX2 orchestrate the trade-offs between proliferation and invasion and govern cancer stem cell dynamics. Corresponding biomarkers\u2014PD-L1, CD163\/CD68 ratios, LAMP3, ALDH\/SOX2, Zeb1, Vimentin, and CD44 isoforms\u2014become far more informative when resolved at single-cell and spatial scales, thereby enabling sharper patient stratification. We then mapped the pathological interplay among tumor, stromal, and immune compartments. Extracellular matrix reprogramming, CAF heterogeneity, and the spatial polarity of immune infiltrates generate discrete micro-niches with distinct functional consequences. Spatial profiling can convert static pathology into a dynamic atlas of therapeutic opportunities. Finally, we outlined translational directions. Targeting inflammation and the microenvironment\u2014via TAM reprogramming, cytokine blockade, or STING\/CD47 pathway modulation combined with immune checkpoint blockade (ICB)\u2014offers a rational strategy to improve outcomes. Altogether, these strategies point toward an ecology-aware approach to precision immunotherapy for HNSCC\u2014one that reads and reshapes the tumor\u2019s inflammatory language rather than ignoring it.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1798938","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T05:45:53Z","timestamp":1784267153000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Inflammation as a master regulator of immunotherapy response in head and neck squamous cell carcinoma: from malignant transformation to ecology-aware precision combinations"],"prefix":"10.3389","volume":"17","author":[{"given":"Yingchen","family":"Han","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, The First Affiliated Hospital of China Medical University","place":["Shenyang, Liaoning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peihong","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, The First Affiliated Hospital of China Medical University","place":["Shenyang, Liaoning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoran","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, The First Affiliated Hospital of China Medical University","place":["Shenyang, Liaoning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruoxi","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, The First Affiliated Hospital of China Medical University","place":["Shenyang, Liaoning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruotong","family":"Liu","sequence":"additional","affiliation":[{"name":"Shenyang Medical College","place":["Shenyang, Liaoning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenguang","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Interventional Medicine, Liaoning Provincial People\u2019s Hospital","place":["Shenyang, Liaoning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaozhe","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Oncology, General Hospital of the Northern Theater Command","place":["Shenyang, Liaoning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, The First Affiliated Hospital of China Medical University","place":["Shenyang, Liaoning, 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