{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T23:32:53Z","timestamp":1776123173151,"version":"3.50.1"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T00:00:00Z","timestamp":1756684800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81972766, 82173336, 81972420"],"award-info":[{"award-number":["81972766, 82173336, 81972420"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Urokinase-type plasminogen activator (uPA) is upregulated in prostate cancer, but its comprehensive impact on the immune microenvironment and the underlying mechanisms remains to be fully elucidated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>uPA expression was analyzed in clinical prostate cancer specimens and correlated with CD8\u207a T cell infiltration. Tumor growth was assessed in the uPA-deficient (uPA<jats:sup>\u2013\/\u2013<\/jats:sup>)and the uPA inhibitor UK122-treated mouse model. Immune infiltration was evaluated by CyTOF and flow cytometry. Anti-CD19 chimeric antigen receptor (CAR)-engineered WT or uPA<jats:sup>\u2013\/\u2013<\/jats:sup> CD8\u207a T cells were tested for cytotoxicity against RM1-CD19 cells. The combination of UK122 and anti-PD-1 therapy was assessed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Elevated uPA in prostate cancer specimens inversely correlated with CD8\u207a T cell infiltration. Both genetic uPA ablation and UK122 significantly attenuated tumor growth by enhancing antitumor immunity. uPA deficiency markedly increased CD8\u207a T cell infiltration. uPA<jats:sup>\u2013\/\u2013<\/jats:sup> CD8\u207a T cells exhibited enhanced cytotoxicity compared to WT CD8\u207a T cells. Tumor-infiltrating uPA<jats:sup>\u2013\/\u2013<\/jats:sup> CD8\u207a T cells showed higher PD-1 expression. UK122 synergized with anti-PD-1 therapy to promote tumor regression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>uPA is a significant immunosuppressive regulator in prostate cancer. Its inhibition enhances CD8\u207a T cell function and synergizes with immune checkpoint blockade, supporting uPA targeting as a novel strategy to improve prostate cancer immunotherapy efficacy.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1625226","type":"journal-article","created":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T05:30:09Z","timestamp":1756704609000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Urokinase-type plasminogen activator deficiency enhances CD8+ T cell infiltration and anti-PD-1 therapy efficacy in prostate 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