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Considerable tumoral heterogeneity exists in GBM, leading to inefficacy of current treatments and the absence of meaningful improvements in frontline therapies in the past 20 years. Through multiomic analysis of patient-derived primary and recurrent GBM cell lines, we identified the urokinase plasminogen activator receptor (uPAR) as a protumorigenic marker of putative brain tumor\u2013initiating cells and a potential therapeutic target. We found that genetic disruption of uPAR expression impaired protumorigenic characteristics in vitro and in vivo, highlighting its biological role in tumorigenesis. We then generated uPAR-specific chimeric antigen receptor (CAR) T cells, which demonstrated potent antitumor activity in recurrent GBM patient\u2013derived xenograft models. In addition to direct tumor cell killing, we found that uPAR is expressed on GBM-associated macrophages, enabling uPAR CAR T cells to target both GBM itself and cells in the tumor microenvironment. Together, these data illustrate the potency and therapeutic potential of targeting uPAR in GBM.<\/jats:p>","DOI":"10.1126\/scitranslmed.aea8381","type":"journal-article","created":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T17:58:22Z","timestamp":1778695102000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":5,"title":["uPAR is highly expressed in recurrent glioblastoma and represents a candidate CAR T cell target"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-5491-3452","authenticated-orcid":true,"given":"William T.","family":"Maich","sequence":"first","affiliation":[{"name":"Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON, Canada."},{"name":"Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad 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