{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T05:17:14Z","timestamp":1778822234425,"version":"3.51.4"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T00:00:00Z","timestamp":1757635200000},"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:p>Prostate cancer is one of the most common malignancies in men and is frequently associated with tumor-promoting inflammation. Tumor-associated macrophages (TAMs) are known to facilitate cancer progression by suppressing antitumor immunity. Therefore, targeting TAMs represents a promising strategy for cancer therapy. This study aimed to investigate whether melittin-dKLA, a conjugated peptide consisting of melittin (MEL), which selectively binds M2-like macrophages, and the pro-apoptotic peptide d(KLAKLAK)<jats:sub>2<\/jats:sub> (dKLA), can inhibit prostate cancer progression by targeting M2 macrophages. Human monocytic cells (THP-1 cells) were differentiated into TAMs using tumor-conditioned medium (TCM), and the conditioned medium from these TAMs was termed M-TCM. MEL-dKLA binding affinity was assessed using FITC-labeled melittin. A prostate cancer mouse model was established by subcutaneous injection of TRAMP-C2 cells, followed by MEL-dKLA administration every three days. As a result, THP-1-derived macrophages stimulated with TCM exhibited elevated expression of M2 markers (ARG1, CD206, and CD163). Prostate cancer cells (PC-3) stimulated with M-TCM showed increased proliferation and expression of epithelial-mesenchymal transition (EMT) markers. MEL-dKLA preferentially bound to M2 macrophages and TAMs, and inducing selective cytotoxicity. Conditioned media from MEL-dKLA-treated M2 macrophages and TAMs resulted in markedly decreased PC-3 cell proliferation, migration, and invasion. <jats:italic>In vivo<\/jats:italic>, MEL-dKLA treatment significantly reduced tumor growth, decreased the number of CD163<jats:sup>+<\/jats:sup> M2 macrophages, and increased CD8<jats:sup>+<\/jats:sup> T cell infiltration in tumor tissues. These findings demonstrate that MEL-dKLA suppresses prostate cancer progression by targeting M2-like TAMs both <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>. MEL-dKLA may serve as a promising therapeutic agent to modulate the tumor microenvironment in prostate cancer.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1652166","type":"journal-article","created":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T05:35:51Z","timestamp":1757655351000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Immunomodulatory peptide\u2013drug conjugate MEL-dKLA suppresses progression of prostate cancer by eliminating M2-like tumor-associated macrophages"],"prefix":"10.3389","volume":"16","author":[{"given":"Ik-Hwan","family":"Han","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ilseob","family":"Choi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Soyoung","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Minjin","family":"Kwon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyojung","family":"Choi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyunsu","family":"Bae","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21660","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA: A Cancer J Clin"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2020.09.042","article-title":"EAU-EANM-ESTRO-ESUR-SIOG guidelines on prostate cancer\u20142020 update. 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