{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T21:35:43Z","timestamp":1775165743270,"version":"3.50.1"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,5,16]],"date-time":"2025-05-16T00:00:00Z","timestamp":1747353600000},"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. Nutr."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>1,25(OH)<jats:sub>2<\/jats:sub>D<jats:sub>3<\/jats:sub> supplementation alone does not provide sufficient benefit to hepatocellular carcinoma (HCC) patients in clinical trials. Tumor-associated macrophages (TAMs)-mediated immunosuppression is regarded as a major hurdle for the effectiveness of several treatments. Previous studies revealed that hCAP18\/LL-37 was an important factor which directly suppresses the anticancer activity of 1,25(OH)<jats:sub>2<\/jats:sub>D<jats:sub>3<\/jats:sub> on HCC cells. However, whether TAMs contribute to the limited clinical efficacy of 1,25(OH)<jats:sub>2<\/jats:sub>D<jats:sub>3<\/jats:sub> through hCAP18\/LL-37 remains unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Co-culture systems of HCC cells (PLC\/PRF-5, Huh7) with THP-1-derived macrophages and co-xenograft mouse models were established. Anticancer activity was evaluated <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> mouse models using standard assays. Mechanistic investigations utilized qRT-PCR, Western blot, flow cytometry, ELISA, and immunohistochemistry. Therapeutic efficacy of 1,25(OH)<jats:sub>2<\/jats:sub>D<jats:sub>3<\/jats:sub>\/suramin combination was assessed in co-xenograft and N-Nitrosodiethylamine (DEN)\/Carbon tetrachloride (CCl<jats:sub>4<\/jats:sub>)-induced HCC models.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>1,25(OH)<jats:sub>2<\/jats:sub>D<jats:sub>3<\/jats:sub> (200\u2013500\u202fnM) promoted macrophage recruitment, M2 polarization, Akt\/mTOR signal and STAT3 signal activation in HCC\/macrophage co-culture systems. This effect was mediated by 1,25(OH)<jats:sub>2<\/jats:sub>D<jats:sub>3<\/jats:sub>-induced hCAP18\/LL-37 overexpression, which facilitated TAM infiltration and M2 reprogramming. Suramin, a potent LL-37 inhibitor, abrogated these immunosuppressive effects by blocking LL-37 internalization, restoring M1 polarization and suppressing Akt\/mTOR and STAT3 pathways. Notably, 1,25(OH)<jats:sub>2<\/jats:sub>D<jats:sub>3<\/jats:sub>\/suramin combination therapy synergistically inhibited HCC proliferation, colony formation, and invasion <jats:italic>in vitro<\/jats:italic>. In xenograft models and DEN\/CCl<jats:sub>4<\/jats:sub>-induced HCC models, suramin enhanced 1,25(OH)<jats:sub>2<\/jats:sub>D<jats:sub>3<\/jats:sub>\u2019s efficacy by promoting M1 polarization, increasing intratumoral M1\/M2 ratios, reducing tumor growth, and diminishing macroscopic nodules.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The 1,25(OH)<jats:sub>2<\/jats:sub>D<jats:sub>3<\/jats:sub>-LL-37-TAM axis drives immunosuppression in HCC by modulating macrophage phenotypes. While suramin potently disrupts this axis, blocking LL-37-mediated TAMs recruitment and M2 polarization, while promoting antitumor M1 phenotype responses. These findings highlight suramin as a promising adjunct to 1,25(OH)<jats:sub>2<\/jats:sub>D<jats:sub>3<\/jats:sub>-based immunotherapy for HCC.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnut.2025.1556533","type":"journal-article","created":{"date-parts":[[2025,5,16]],"date-time":"2025-05-16T04:11:30Z","timestamp":1747368690000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Suramin blocked hCAP18\/LL-37-induced macrophage recruitment and M2 polarization to enhance the therapeutic efficacy of 1,25(OH)2D3 against hepatocellular carcinoma in vitro and in vivo mouse 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