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Tumor\u2010reactive T\u2010cell states are increasingly recognized as critical determinants of antitumor immunity; however, progression\u2010associated T\u2010cell programs that reflect tumor evolution and predict immunotherapy benefit remain insufficiently characterized. We integrated single\u2010cell transcriptomic and T\u2010cell receptor (TCR) sequencing data from HPV\u2010negative HNSCC progression models to identify T\u2010cell genes associated with tumor progression and TCR\u2010supported immune states. Candidate genes were further refined using pretreatment immunotherapy cohorts, and a five\u2010gene signature (HNSC\u2010TstcSig) was established using survival and response\u2010associated analyses. The predictive performance of HNSC\u2010TstcSig was evaluated across multiple immunotherapy cohorts, including HNSCC and melanoma data sets. Single\u2010cell transcriptomic analyses, spatial transcriptomic analysis, and multiplex immunofluorescence were performed to characterize the biological features of HNSC\u2010TstcSig\u2010associated immune states. In addition, machine learning\u2010based survival modeling was conducted to identify genes shared between immunotherapy response and natural prognosis. HNSC\u2010TstcSig, consisting of GBP2, HAVCR2, ETV7, ICOS, and IL2RA, showed consistent associations with immunotherapy response across multiple cohorts and reflected an immune\u2010inflamed tumor microenvironment characterized by enhanced immune infiltration, T\u2010cell activation, and immune checkpoint\u2010related programs. Single\u2010cell analyses revealed that HNSC\u2010TstcSig genes were predominantly enriched in activated CD8 T\u2010cell populations and were associated with cytotoxic and inflammatory immune states. Among the signature genes, ICOS showed consistent associations with CD8 T\u2010cell activation, cytotoxicity, and immune checkpoint\u2010related features. Network perturbation analysis further suggested that ICOS was connected with transcriptional programs involved in T\u2010cell functional regulation. Spatial transcriptomic analysis and multiplex immunofluorescence further supported the association between ICOS\u2010related immune features and tumor immune activity at the tissue level. Furthermore, a machine learning\u2010derived natural prognostic model identified ICOS as a shared gene linking immunotherapy response and survival outcomes. We developed a progression\u2010associated T\u2010cell signature, HNSC\u2010TstcSig, that predicts immunotherapy response and reflects immune\u2010active tumor states in HNSCC. Our findings suggest that ICOS is associated with a tumor\u2010reactive CD8 T\u2010cell state characterized by cytotoxic activity and immune checkpoint\u2010related features, providing a potential biomarker for immune stratification and a framework for understanding T\u2010cell states associated with therapeutic benefit.<\/jats:p>","DOI":"10.1002\/mc.70185","type":"journal-article","created":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T18:25:18Z","timestamp":1790533518000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Progression\u2010Associated Tumor\u2010Reactive T\u2010Cell Signature Predicts Immunotherapy Response and Reveals ICOS\u2010High CD8 T\u2010Cell Functional States in Head and Neck Squamous Cell Carcinoma"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-9419-6939","authenticated-orcid":false,"given":"Shaoqian","family":"Zhang","sequence":"first","affiliation":[{"name":"Medical Research Center, Beijing Chao\u2010Yang Hospital Capital Medical University Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaotong","family":"Yan","sequence":"additional","affiliation":[{"name":"National Cancer Center\/National Clinical Research Center for Cancer\/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3282-7929","authenticated-orcid":false,"given":"Xichen","family":"Dong","sequence":"additional","affiliation":[{"name":"Medical Research Center, Beijing Chao\u2010Yang Hospital Capital Medical University Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8353-4547","authenticated-orcid":false,"given":"Changming","family":"An","sequence":"additional","affiliation":[{"name":"National Cancer Center\/National Clinical Research Center for Cancer\/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Oncology First Hospital of Qinhuangdao Qinhuangdao Hebei Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Wen","sequence":"additional","affiliation":[{"name":"Medical Research Center, Beijing Chao\u2010Yang Hospital Capital Medical University Beijing 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