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This specialized microenvironment not only promotes leukemia cell survival, but also inhibits T cell infiltration, which serves as a major obstacle to the effectiveness of CAR\u2010T therapy in myeloid malignancies. To overcome this limitation, we targeted Rac1 GTPase, a central regulator of cytoskeletal dynamics that controls membrane protrusion and migration, by engineering primary human T cells and CD33 CAR\u2010T cells to express constitutively active Rac1 (Rac1V12). Our results demonstrated that active Rac1 enhanced the migration of T cells and CD33 CAR\u2010T cells and promoted their residence in the BM in\u00a0vivo. Furthermore, CD33 CAR\u2010T cells expressing Rac1V12 displayed enhanced cytotoxicity against leukemia cells in\u00a0vitro, as demonstrated by transwell migration\u2010dependent killing assays. Crucially, these engineered CAR\u2010T cells achieved superior robust suppression of leukemia in\u00a0vivo and significantly prolonged survival in xenograft models. Mechanistically, Rac1V12 CD33 CAR\u2010T cells in the BM demonstrated enhanced immunological memory phenotype and lower tonic signaling, a combination that promotes T cell persistence and enhances anti\u2010tumor efficacy in\u00a0vivo. Our data suggest that active Rac1\u2010engineered CD33 CAR\u2010T cells represent a novel strategy for targeting BM leukemia cells, with the potential to eradicate AML cells.<\/jats:p>","DOI":"10.1096\/fj.202503832rr","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T15:11:56Z","timestamp":1775833916000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Active Rac1\u2010Mediated Bone Marrow Retention Enhances\n                    <scp>CD33 CAR<\/scp>\n                    \u2010T Cell Efficacy Against\n                    <scp>CD33<\/scp>\n                    <sup>+<\/sup>\n                    Leukemia Cells"],"prefix":"10.1096","volume":"40","author":[{"given":"Shangshang","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Tianjin Key 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