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Here, genetic targeting of CBL-B enhances the performance of adoptively transferred T cells and CAR T cells under tumor microenvironment-like stress. In fully immunocompetent mouse models, Cblb deficiency or transient Cblb silencing improves control of MC-38 colon carcinoma and autochthonous mammary tumors, demonstrating that CBL-B restrains anti-tumor immunity. Cblb-deficient T cells show enhanced expansion and effector\/effector-memory differentiation during an in vivo mixed lymphocyte reaction, confirming a cell-intrinsic brake function of CBL-B during sustained antigenic challenge. In a syngeneic Panc02-EpCAM model, Cblb-deficient anti-EpCAM CAR T cells show superior tumor control, enhanced infiltration, prolonged survival, and preserved effector function despite chronic antigen exposure and TGF-\u03b2. Mechanistically, Cblb targeting maintains granzyme B and IFN-\u03b3 production and is associated in vitro with increased GSDME-linked pyroptotic tumor cell death, consistent with features of immunogenic cell death. These findings extend previous CBL-B CAR T work from lymphocyte-deficient to immunocompetent settings and support CBL-B inhibition as a strategy to engineer CAR T cells that resist suppressive tumor microenvironments while promoting a more inflammatory mode of tumor killing.<\/jats:p>","DOI":"10.3390\/cells15151407","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T15:51:23Z","timestamp":1785772283000},"page":"1407","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Cblb Gene Editing in T Cells Sustains Expansion and Immunogenic CAR T Tumor Killing Under Chronic Antigenic Stimulation"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-7507-9603","authenticated-orcid":false,"given":"Daniel","family":"Schreiber","sequence":"first","affiliation":[{"name":"Institute for Cell Genetics, Medical University of Innsbruck, 6020 Innsbruck, 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Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5844-7329","authenticated-orcid":false,"given":"Alexander","family":"Dohnal","sequence":"additional","affiliation":[{"name":"invIOs GmbH, Campus-Vienna-Biocenter, 1030 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romana","family":"Gugenberger","sequence":"additional","affiliation":[{"name":"invIOs GmbH, Campus-Vienna-Biocenter, 1030 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5796-7090","authenticated-orcid":false,"given":"Thomas","family":"Gruber","sequence":"additional","affiliation":[{"name":"Institute for Cell Genetics, Medical University of Innsbruck, 6020 Innsbruck, 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