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Our research identified G protein\u2013coupled receptor 65 (GPR65) as a tumor-specific determinant affecting the efficacy of CAR T-cell therapy. In human patients and an immune-competent mouse model of B-cell acute lymphoblastic leukemia, low GPR65 expression correlates with resistance to CD19+ CAR T treatment. GPR65 knockout (GPR65 KO) tumors in mice similarly exhibit resistance. Through single-cell network analyses, we discovered that GPR65 deficiency reshapes tumor interactions with host macrophages by increasing tumor VEGFA levels, leading to macrophage expansion and preferential M2 polarization. Depleting host macrophages or deleting VEGFA in GPR65 KO tumors restores CAR T-cell therapy responsiveness. Moreover, combining anti-VEGFA therapy with CAR T-cell treatment significantly prolongs the survival of mice bearing GPR65 KO tumors. These findings emphasize the profound impact of tumor gene expression on the tumor microenvironment and subsequent CAR T-cell therapy outcomes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>The study identifies GPR65 as an important determinant of B-cell acute lymphoblastic leukemia response to CAR T-cell therapy. Notably, GPR65 absence signals CAR T resistance. By emphasizing the therapeutic potential of targeting VEGFA or host macrophages, our study identifies routes to optimize CAR T-cell therapy outcomes in hematologic malignancies via tumor microenvironment manipulation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-24-0841","type":"journal-article","created":{"date-parts":[[2025,2,25]],"date-time":"2025-02-25T10:02:31Z","timestamp":1740477751000},"page":"1018-1036","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["GPR65 Inactivation in Tumor Cells Drives Antigen-Independent CAR T-cell Resistance via Macrophage Remodeling"],"prefix":"10.1158","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9288-1025","authenticated-orcid":false,"given":"Jayadev","family":"Mavuluri","sequence":"first","affiliation":[{"name":"1Department of Pathology, St. Jude Children\u2019s Research Hospital, Memphis, 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