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We developed a CD24\u2009\u00d7\u2009CD3 bispecific antibody (CD24 BsAb) and CXCR3-armed CD24 CAR-T cells, both exhibiting potent antitumor activity in lymphoma and leukemia models. CD24 BsAb and CD24 CAR-T overcome CD19 CAR-T resistance driven by antigen loss and apoptosis defects in vitro and in vivo. Beyond direct cytotoxicity, CD24-targeted T cells reprogram macrophages toward an M1-like phenotype and enhance phagocytic clearance. We further engineered a dual-specific, dual-functional CD19 CAR-T that secretes a CD24 bispecific T-cell engager (CD24 BiTE), enabling simultaneous targeting of CD19 and CD24 to address tumor heterogeneity and achieve superior efficacy. Collectively, our study demonstrates that CD24-directed adoptive T-cell therapies are warranted for B-cell malignancies through robust induction of both innate and adaptive immune responses.<\/jats:p>","DOI":"10.1038\/s41375-026-03159-y","type":"journal-article","created":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T17:08:18Z","timestamp":1791824898000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Combating CD24 to overcome CD19 CAR-T resistance via induction of innate and adaptive immunity in B-cell malignancies"],"prefix":"10.1038","author":[{"given":"Qing","family":"Yin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1919-4831","authenticated-orcid":false,"given":"Xiangao","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allen","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Xiong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1295-3258","authenticated-orcid":false,"given":"Jeffrey W.","family":"Craig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Loryn","family":"Blackburn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8709-8762","authenticated-orcid":false,"given":"Amy S.","family":"Schienschang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah A.","family":"Whitaker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Archana","family":"Thakur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9487-8345","authenticated-orcid":false,"given":"Craig A.","family":"Portell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3249-9796","authenticated-orcid":false,"given":"Daniel W.","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shane","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lawrence G.","family":"Lum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Selina","family":"Chen-Kiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5981-9983","authenticated-orcid":false,"given":"Michael E.","family":"Williams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7632-1594","authenticated-orcid":false,"given":"Jianguo","family":"Tao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,12]]},"reference":[{"key":"3159_CR1","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/j.tmrv.2016.03.001","volume":"30","author":"A Fesnak","year":"2016","unstructured":"Fesnak A, Lin C, Siegel DL, Maus MV. 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Craig: consultant and expert testimony for Bayer; Honoraria from BeiGene\/BeOne. C.A. Portell: consultant for AbbVie, Astra Zeneca, BeiGene\/BeOne, Genentech, Jansen, Merck, Pfizer and receiving research support from AbbVie, AstraZeneca, Acerta, BeiGene\/BeiOne, Merck, SeaGen\/Pfizer, Loxo\/Lilly, Genentech. M.E. Williams: consultant\/advisory board for AstraZeneca, Beigene\/BeOne, Janssen and receiving grant\/research support from Janssen. D.W. Lee is a consultant for Clasp Therapeutics, Pierre Fabre Pharmaceuticals, Merck, and Harpoon Therapeutics, receives research support from Kite Pharma\/Gilead, and holds CAR-T related patents. J. Tao is a founder of NewPath Therapeutics, LLC. L.G. Lum is co-founder of Transtarget, Inc, Scientific Board Member of Rapa Therapeutics, and Tundra Therapeutics, and Founder of BATs, LLC, and BiTCel, LLC. The remaining authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"All methods were performed in accordance with relevant guidelines and regulations. All animal studies were approved by the Institutional Animal Care and Use Committee (IACUC) of the University of Virginia (protocol number: 4453). Human peripheral blood mononuclear cells (PBMCs) were obtained under protocols approved by the Institutional Review Board (IRB) of the University of Virginia (protocol number: 00000447), and written informed consent was obtained from all participants.","order":2,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Ethics"}}]}}