The study shows that taking high‑dose vitamin D (the form 1,25‑OH2‑D3) can boost a protein called LL‑37, which then attracts immune cells that actually help liver cancer grow. Adding the drug suramin blocks LL‑37, shifts those immune cells to a cancer‑fighting type, and makes vitamin D work better against tumors in mice. This is all done in cell cultures and mouse models, not in people.

1,25(OH)₂D₃ 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)₂D₃ on HCC cells. However, whether TAMs contribute to the limited clinical efficacy of 1,25(OH)₂D₃ through hCAP18/LL-37 remains unclear. 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 <i>in vitro</i> and <i>in vivo</i> mouse models using standard assays. Mechanistic investigations utilized qRT-PCR, Western blot, flow cytometry, ELISA, and immunohistochemistry. Therapeutic efficacy of 1,25(OH)₂D₃/suramin combination was assessed in co-xenograft and N-Nitrosodiethylamine (DEN)/Carbon tetrachloride (CCl₄)-induced HCC models. 1,25(OH)₂D₃ (200-500&#x202f;nM) 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)₂D₃-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)₂D₃/suramin combination therapy synergistically inhibited HCC proliferation, colony formation, and invasion <i>in vitro</i>. In xenograft models and DEN/CCl₄-induced HCC models, suramin enhanced 1,25(OH)₂D₃'s efficacy by promoting M1 polarization, increasing intratumoral M1/M2 ratios, reducing tumor growth, and diminishing macroscopic nodules. The 1,25(OH)₂D₃-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)₂D₃-based immunotherapy for HCC.