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In this work, we developed a series of novel CAR \u03b3\u03b4 T cells redirected to B\u2010cell maturation antigen (BCMA) and performed functional assays compared to CAR \u03b1\u03b2 T cells. As a result, novel CAR \u03b3\u03b4 T cells demonstrated similar activation upon antigen stimulation compared with CAR \u03b1\u03b2 T cells but showed lower proliferative capacity and less durable cytotoxicity. In\u00a0vivo, higher doses of CAR \u03b3\u03b4 T cells were required to achieve tumour control comparable to CAR \u03b1\u03b2 T cells. Among CAR constructs, those with cluster of differentiation 3 (CD3\u03b5 or CD3\u03b6) intracellular domain exhibited superior cytotoxicity and in\u00a0vivo efficacy. Single\u2010cell transcriptomic profiling revealed the low ratio of cycling CAR \u03b3\u03b4 T cells after antigen stimulation limited the persistence of CAR \u03b3\u03b4 T cells. In conclusion, our developed novel CAR \u03b3\u03b4 T cells effectively eliminated MM cells in\u00a0vitro, but exhibited limited in\u00a0vivo persistence compared to traditional CAR \u03b1\u03b2T cells. These findings establish a baseline for utilizing \u03b3\u03b4 T cells as an off\u2010the\u2010shelf platform and highlight that addressing the proliferation bottleneck through further engineering is essential for future clinical translation.<\/jats:p>","DOI":"10.1111\/bjh.70660","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T06:33:57Z","timestamp":1783924437000},"page":"998-1009","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The development of novel chimeric antigen receptor gamma\u2010delta T cells against multiple myeloma and single\u2010cell RNA sequencing analysis"],"prefix":"10.1111","volume":"209","author":[{"given":"Yang","family":"Hong","sequence":"first","affiliation":[{"name":"Department of Hematology Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cuiling","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Hematology Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jue","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Hematology Nanjing Drum Tower Hospital, Clinical College of Nanjing University of Chinese Medicine  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhua","family":"Zhang","sequence":"additional","affiliation":[{"name":"Isao Biotherapeutics Co. 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