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While CAR T cell therapy has shown promise in hematologic malignancies, its application in solid tumors is limited by poor trafficking and on-target off-tumor toxicities. Here, we identify and validate MUC16 as a clinically relevant target for BCa, noting enriched expression in tumors recalcitrant to existing therapies. We engineered a second-generation mesothelin-based CAR (MSLN-28z) and demonstrated robust activity across multiple BCa cell lines and patient-derived tumor organoids. Intravesical delivery of MSLN-28z CAR T cells in xenograft BCa models conferred superior tumor control compared with intravenous transfer, while attenuating systemic T cell engraftment. Intravesical adoptive transfer uncouples local antitumor efficacy from potential systemic toxicity\u2014a feature conserved across several T cell immunotherapies with on-target off-tumor activity. Collectively, these findings substantiate MUC16 as a therapeutic candidate and validate intravesical delivery as a platform for T cell immunotherapies in the management of organ-confined BCa.<\/jats:p>","DOI":"10.1084\/jem.20250699","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T06:21:08Z","timestamp":1777443668000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["Intravesical mesothelin-based CAR T cells targeting MUC16 effectively control bladder cancer in preclinical models"],"prefix":"10.1084","volume":"223","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1636-6579","authenticated-orcid":true,"given":"Parwiz","family":"Abrahimi","sequence":"first","affiliation":[{"name":"Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 1 Departments of Urology and Biomedical Sciences, Los Angeles, 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