{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T23:54:37Z","timestamp":1784159677502,"version":"3.55.0"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T00:00:00Z","timestamp":1747785600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Castration-resistant prostate cancer (CRPC) has a poor prognosis and requires novel therapeutic approaches. Previously, we discovered that a high dose of human peripheral blood-derived natural killer (PB-NK) cells can have antitumor effects against CRPC. However, whether antibodies against prostate-specific membrane antigen (PSMA) can direct adoptive NK cells to the tumor site and therefore decrease NK cell dosage through antibody-dependent cellular cytotoxicity remains unknown.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>NK cells were obtained from the blood samples of healthy donors. To engineer an anti-PSMA antibody (Ab), a llama was immunized with human PSMA protein, and the anti-PSMA variable domains of camelid heavy-chain antibody (VHH) clones were isolated using phage display. The VHH was recombinantly fused with the human Fc region to produce an anti-PSMA Ab. <jats:italic>In vitro<\/jats:italic>, NK cell cytotoxicity was evaluated using cell counting kit-8. Levels of cytokines and prostate-specific antigen (PSA) were determined using ELISA. The expression of CD107a and CD16 (the Ab Fc-receptor) in NK cells and the Ab affinity were detected using flow cytometry. Antitumor effects were evaluated in patient-derived organoid (PDO) models and in 22RV1 tumor-bearing mice <jats:italic>in vivo<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We constructed an anti-PSMA Ab and validated its high affinity toward the PSMA antigen. CD16 is abundantly expressed in PB-NK cells. The anti-PSMA Ab significantly enhanced the cytotoxicity of NK cells against CRPC cells <jats:italic>in vitro<\/jats:italic>, evidenced by increased killing rate, upregulation of the degranulation marker CD107a, increased secretion of interferon-\u03b3, and decreased PSA levels. Furthermore, our combined treatment showed powerful antitumor effects in PDO and CRPC xenograft mouse models.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Combined treatment with anti-PSMA Ab and human PB-NK cells improves antitumor efficacy against CRPC and is a promising approach to treating CRPC in clinical settings.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1572676","type":"journal-article","created":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T05:24:29Z","timestamp":1747805069000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Combined treatment with anti-PSMA antibody and human peripheral blood-derived NK cells for castration-resistant prostate 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