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By integrating public single\u2010cell RNA sequencing analysis with experimental validation, we identify the transcription factor FOXP1 as a critical brake limiting Th9 CAR\u2010T cell differentiation and effector programming. FOXP1 knockdown reprograms Th9 CAR\u2010T but not Tc9 cells toward a metabolically active, cytotoxic, and exhaustion\u2010resistant phenotype, thereby enhancing their persistence and antitumor activity. CUT&amp;Tag and transcriptomic profiling reveal that FOXP1 binds regulatory regions of\n                    <jats:italic>Il9<\/jats:italic>\n                    ,\n                    <jats:italic>Spi1<\/jats:italic>\n                    , and\n                    <jats:italic>Runx1<\/jats:italic>\n                    , as well as effector loci such as\n                    <jats:italic>Tnf<\/jats:italic>\n                    and\n                    <jats:italic>Gzmb<\/jats:italic>\n                    , repressing both Th9\u2010lineage and TCR\u2010downstream transcriptional programs. Its depletion releases this repression, broadly activating MAPK, PI3K\u2010Akt\/mTOR, and NF\u2010\u03baB pathways that sustain cytokine production and memory formation. Functionally, FOXP1\u2010deficient Th9 CAR\u2010T cells eradicate both antigen\u2010positive and antigen\u2010loss tumor populations by recruiting dendritic cells and promoting endogenous CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell clonal expansion via the CD6\u2010Flt3L axis. Our findings establish FOXP1 as a transcriptional checkpoint integrating cytokine and signaling networks to control Th9 CAR\u2010T cell function and provide a mechanistic rationale for engineering CAR\u2010T therapies capable of overcoming antigen escape.\n                  <\/jats:p>","DOI":"10.1002\/advs.77564","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T04:16:34Z","timestamp":1789618594000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["FOXP1 Knockdown Reprograms Th9 CAR\u2010T Cells to Overcome Antigen Escape"],"prefix":"10.1002","author":[{"given":"Yihan","family":"Zhu","sequence":"first","affiliation":[{"name":"Department of Urology Zhujiang Hospital Southern Medical University  Guangzhou China"},{"name":"Department of Biochemistry and Molecular Biology School of Basic Medical Sciences Southern Medical University  Guangzhou Guangdong 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