{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T20:43:02Z","timestamp":1792096982827,"version":"4.4.0"},"reference-count":42,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T00:00:00Z","timestamp":1756944000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Tumor-associated macrophages (TAMs) are one of the most important components of the tumor microenvironment and play a critical role in promoting tumor invasion and metastasis. These cells have become a new therapeutic target for inhibiting tumor progression. Lysine\/leucine-rich antimicrobial peptides have well-documented anticancer activity in vitro, but their immune regulatory activity in human macrophages is not clear. The present study investigated the regulatory effects of lysine\/leucine-rich peptides on the polarization of M2-like macrophages and the metastasis of breast cancer cells mediated by M2-like TAMs in the tumor microenvironment (TME). Our results revealed remarkable inhibition of the polarization of M2-like macrophages following treatment with lysine\/leucine-rich antimicrobial peptides, which was accompanied by a significant reduction in the expression of the M2-like macrophage-specific factors interleukin-10 (IL-10) and transforming growth factor-\u03b2 (TGF-\u03b21) and the M2 macrophage-specific marker CD206. The lysine\/leucine-rich antimicrobial peptides downregulated the expression of PPAR\u03b3 and Kr\u00fcppel-like factor 4 (KLF4) and the phosphorylation of STAT6 in the STAT6 signaling pathway, which resulted in a decrease in IL-10 and TGF-\u03b21. Moreover, we found that lysine\/leucine-rich antimicrobial peptide-treated macrophages reduced the migration of cancer cells by inhibiting the phosphorylation of the mTOR, smad2 and ERK proteins during tumor metastasis. These findings highlight the potential of lysine\/leucine-rich antimicrobial peptides as therapeutic agents that target M2-like macrophages to inhibit cancer cell metastasis.<\/jats:p>","DOI":"10.3390\/ijms26178627","type":"journal-article","created":{"date-parts":[[2025,9,5]],"date-time":"2025-09-05T07:46:17Z","timestamp":1757058377000},"page":"8627","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Lysine-Leucine-Rich Frog Skin Antimicrobial Peptides Inhibit Breast Cancer Metastasis by Reprogramming Tumor-Associated Macrophage Polarization"],"prefix":"10.3390","volume":"26","author":[{"given":"Zhenyan","family":"Li","sequence":"first","affiliation":[{"name":"School of Life Science, Liaoning Normal University, Dalian 116081, China"},{"name":"School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuan","family":"Zhou","sequence":"additional","affiliation":[{"name":"School of Life Science, Liaoning Normal University, Dalian 116081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weibing","family":"Dong","sequence":"additional","affiliation":[{"name":"School of Life Science, Liaoning Normal University, Dalian 116081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ang","family":"Li","sequence":"additional","affiliation":[{"name":"School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China"},{"name":"School of Basic Medical Sciences, Dalian University of Technology, Dalian 116024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"106535","DOI":"10.1016\/j.intimp.2020.106535","article-title":"Breast cancer: Biology, biomarkers, and treatments","volume":"84","author":"Barzaman","year":"2020","journal-title":"Int. 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