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Here, we identify Z-DNA binding protein 1 (ZBP1) as a key immunoregulator that reprograms immune-suppressive TMEs. Integrated TCGA\/SangerBox analyses revealed ZBP1 as a hub gene strongly correlated with cytotoxic CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells (r\u2009=\u20090.48,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.0001) and M1 macrophages (r\u2009=\u20090.39,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.0001). Multi-model validation in 92 HNSCC specimens revealed elevated ZBP1 expression versus normal tissues (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.01), co-localized with infiltrating CD8\n                    <jats:sup>+<\/jats:sup>\n                    \/CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells and CD68\n                    <jats:sup>+<\/jats:sup>\n                    macrophages through multiplex immunofluorescence. Clinically, high ZBP1 predicted improved survival (HR\u2009=\u20090.61 for overall survival; HR\u2009=\u20090.45 for disease specific survival;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.0001) and early-stage presentation (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.004). Mechanistically, ZBP1 overexpression in SCC-7\/MOC2 models suppressed tumor growth while enhancing IFN-\u03b3\n                    <jats:sup>+<\/jats:sup>\n                    CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell activation and reducing M2 polarization (CD206\n                    <jats:sup>+<\/jats:sup>\n                    : 16.91% vs 38.19% in ZBP1-high vs control,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001). Single-cell transcriptomics uncovered ZBP1-driven TME remodeling through chemokine signaling networks and expanded effector T cell compartments, validated by 1.49-fold increased CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell infiltration via flow cytometry. Spatial analysis revealed ZBP1 overexpression amplified immune cell crosstalk (1.65-fold interaction increase,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001), upregulating CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell chemotaxis (CXCR3\/CCR5-CCL5 axis) and effector functions (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.0001). Concurrently, it suppressed immunosuppressive pathways through metabolic reprogramming, establishing ZBP1 as a dual regulator synchronizing lymphocyte recruitment and myeloid suppression. Our integrative approach bridges computational biology with functional validation, demonstrating ZBP1\u2019s capacity to convert \u201ccold\u201d tumors into immunologically active niches. This work positions ZBP1 as both a stratification biomarker for checkpoint inhibitor response and a therapeutic target for TME reprogramming in HNSCC.\n                  <\/jats:p>","DOI":"10.1371\/journal.pgen.1012107","type":"journal-article","created":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T17:39:47Z","timestamp":1779817187000},"page":"e1012107","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["ZBP1 Drives CD8+ T cell-mediated anti-tumor immunity in head and neck squamous cell carcinoma"],"prefix":"10.1371","volume":"22","author":[{"given":"Yu","family":"Min","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ge","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lianlian","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shihong","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheran","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingchen","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8448-3043","authenticated-orcid":true,"given":"Lei","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,5,26]]},"reference":[{"issue":"3","key":"pgen.1012107.ref001","first-page":"209","article-title":"Global 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