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Although chimeric antigen receptor (CAR) T\u2010cell therapy dramatically improved outcomes in acute lymphoblastic leukemia (ALL), its efficacy in CLL is limited. We hypothesize that this disparity results from pronounced CAR T\u2010cell exhaustion and the immunosuppressive tumor microenvironment (TME) in CLL. We utilized an autologous 3D TME co\u2010culture model to investigate the functionality of CAR T cells derived from CLL and ALL patients within physiologically relevant conditions. Our results revealed increased exhaustion levels and diminished cytotoxicity of CAR T cells from CLL patients compared to those from ALL patients. Importantly, combining CAR T\u2010cell treatment with interleukin\u201010 (IL\u201010) or CXCR4 blockade effectively improved cytotoxicity against CLL cells, even in stromal\u2010protected regions within the 3D model. These findings offer insights into CAR T\u2010cell dysfunction in CLL and support novel TME\u2010targeted combination strategies to improve clinical outcomes.<\/jats:p>","DOI":"10.1002\/hem3.70279","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T14:34:29Z","timestamp":1765204469000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Functional differences between CLL\u2010 and ALL\u2010derived CAR T cells in a 3D tumor microenvironment highlight CXCR4 and IL\u201010 as potential modulatory targets"],"prefix":"10.1002","volume":"9","author":[{"given":"Janin","family":"Dingfelder","sequence":"first","affiliation":[{"name":"Department of Internal Medicine 5, Hematology and Oncology Universit\u00e4tsklinikum Erlangen Friedrich\u2010Alexander\u2010Universit\u00e4t Erlangen\u2010N\u00fcrnberg (FAU) Erlangen Germany"},{"name":"Bavarian Cancer Research Center (BZKF) Erlangen 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