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This study identifies differentially expressed genes (DEGs) between ROS1 mutated (<jats:italic>ROS1<\/jats:italic>\n            <jats:sup>MUT<\/jats:sup>) and wild-type (<jats:italic>ROS1<\/jats:italic>\n            <jats:sup>WT<\/jats:sup>) LUSC samples from the TCGA database. Using WGCNA, immune-related DEGs (IRGs) were screened. Prognostic signatures derived from IRGs were used to compare immune infiltration, chemotherapy sensitivity, and immune-phenotyping score (IPS) between high- and low-risk subgroups. Hub gene abundance in different cell clusters was analyzed via Sc-seq. TAGAP overexpression or silencing was employed to assess its impact on cytokines production and differentiation of CD4+\u2009T cells, downstream c-Rel expression, and tumor progression. High-risk subgroups exhibited decreased infiltration of natural killer, follicular helper T, and CD8+\u2009T cells, but increased plasma, CD4+\u2009memory resting T, and macrophage M2 cells. These subgroups were more sensitive to Sunitinib and CTLA4 blockade. TAGAP expression was significantly reduced in LUSC. Overexpressing TAGAP enhanced CD4+\u2009T cells to produce cytokines, promoted differentiation into Th1\/Th17 cells, inhibited Treg conversion, and suppressed LUSC cell phenotype in vitro. TAGAP overexpression in CD4+\u2009T cells also inhibited LUSC tumor growth and boosted immune infiltration in vivo. TAGAP\u2019s effects on CD4+\u2009T cells were partly reversed by c-Rel overexpression, highlighting TAGAP's role in rejuvenating CD4+\u2009T cells and exerting anticancer effects by inhibiting c-Rel. This study elucidates the novel therapeutic potential of targeting TAGAP to modulate CD4+\u2009T cell activity in immunotherapy for LUSC.<\/jats:p>","DOI":"10.1007\/s00262-025-03960-1","type":"journal-article","created":{"date-parts":[[2025,2,25]],"date-time":"2025-02-25T14:25:18Z","timestamp":1740493518000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Harnessing TAGAP to improve immunotherapy for lung squamous carcinoma treatment by targeting c-Rel in CD4+\u2009T cells"],"prefix":"10.1007","volume":"74","author":[{"given":"Peian","family":"Cai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haibo","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tongmeng","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huawei","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dejing","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaopei","family":"Hao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenqun","family":"Xing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guanghui","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,2,25]]},"reference":[{"key":"3960_CR1","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3322\/caac.21708","volume":"72","author":"RL Siegel","year":"2022","unstructured":"Siegel RL, Miller KD, Fuchs HE, Jemal A (2022) Cancer statistics, 2022. 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