Lysine-Leucine-Rich Frog Skin Antimicrobial Peptides Inhibit Breast Cancer Metastasis by Reprogramming Tumor-Associated Macrophage Polarization

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-β (TGF-β1) and the M2 macrophage-specific marker CD206. The lysine/leucine-rich antimicrobial peptides downregulated the expression of PPARγ and Krüppel-like factor 4 (KLF4) and the phosphorylation of STAT6 in the STAT6 signaling pathway, which resulted in a decrease in IL-10 and TGF-β1. 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.