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To enhance the therapeutic efficacy of anti\u2010CD19 CAR (CAR19)\u2010T cells, we overexpressed CXCR4 in CAR19\u2010T cells to improve their trafficking to bone marrow (BM), a key sanctuary for minimal residual disease. We engineered CAR19\u2010T cells with overexpression of wild\u2010type CXCR4 (CAR19\/CXCR4\n                    <jats:sup>WT<\/jats:sup>\n                    \u2010T) or gain\u2010of\u2010function CXCR4 S338X mutant (CAR19\/CXCR4\n                    <jats:sup>S338X<\/jats:sup>\n                    \u2010T). Both CAR19\/CXCR4\n                    <jats:sup>WT<\/jats:sup>\n                    \u2010T and CAR19\/CXCR4\n                    <jats:sup>S338X<\/jats:sup>\n                    \u2010T cells exhibited enhanced CXCR4 surface expression in\u00a0vitro and in\u00a0vivo compared to control CAR19\u2010T cells, with the latter showing significantly superior improvements under all tested conditions, including engagement with CAR\u2010specific antigens or CXCR4 ligand CXCL12. Upon engagement with CXCL12, CAR19\/CXCR4\n                    <jats:sup>S338X<\/jats:sup>\n                    \u2010T cells, but not CAR19\/CXCR4\n                    <jats:sup>WT<\/jats:sup>\n                    \u2010T cells, displayed significantly increased activation of ERK1\/2 and AKT signaling pathways, as well as elevated transcription of TNF\u2010\u03b1, IFN\u2010\u03b3, granzyme B, CDK6, and BCL2A1, along with strengthened effector functions, chemotaxis, and activation of anti\u2010apoptotic pathways. Furthermore, CAR19\/CXCR4\n                    <jats:sup>S338X<\/jats:sup>\n                    \u2010T cells demonstrated significantly improved migration to and retention in the BM accompanied by increased CD45RA\n                    <jats:sup>+<\/jats:sup>\n                    CCR7\n                    <jats:sup>+<\/jats:sup>\n                    memory T cell populations, which correlated with enhanced anti\u2010leukemic effects following injection into B\u2010ALL\u2010bearing mice. This study offers a potentially effective strategy to improve the functionality and durability of CAR\u2010T cell responses in hematological malignancies.\n                  <\/jats:p>","DOI":"10.1111\/cas.70313","type":"journal-article","created":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T12:26:54Z","timestamp":1767097614000},"page":"613-630","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Expression of the CXCR4 S338X Variant Improves Anti\u2010Leukemia Efficacy of Anti\u2010\n                    <scp>CD19 CAR<\/scp>\n                    \u2010T Cells"],"prefix":"10.1111","volume":"117","author":[{"given":"Yushu","family":"Mao","sequence":"first","affiliation":[{"name":"Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education the First Hospital of Jilin University  Changchun Jilin China"},{"name":"National\u2010Local Joint Engineering Laboratory of Animal Models for Human 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