The study shows that the antimicrobial peptide LL‑37 can make liver cancer cells release signals (M‑CSF and MCP‑1) that push immune cells (macrophages) into a type that actually helps tumors grow. This effect works through a receptor called FPR2 and leads to more aggressive cancer behavior in lab and mouse experiments.

Cancer cells recruit monocytes, macrophages and other inflammatory cells by producing abundant chemoattractants and growth factors, such as macrophage colony-stimulating factor (M-CSF/CSF-1) and monocyte chemoattractant protein-1 (MCP-1/CCL2), to promote tumor growth and dissemination. An understanding of the mechanisms that target cancer cells and regulate tumor microenvironment is essential in designing anticancer therapies. Here, we showed that serum amyloid-A (SAA) and cathelicidin (LL-37) stimulated M-CSF and MCP-1 expression with or without lipopolysaccharide (LPS) administration; conversely, lipoxin-A(4) (LXA(4)) and annexin-A1 (ANXA1) inhibited LPS-induced M-CSF and MCP-1 production by human (HepG2) and mouse (H22) hepatocellular carcinoma cells (HCCs). The effects of LXA(4), ANXA1, SAA and LL-37 were dependent on the activation of their mutual cell-surface receptor formyl peptide receptor-2 (FPR2) and subsequent ROS-MAPK-NF-kB signalings. Furthermore, our results indicated that LPS switched macrophages into an IL-10(low)IL-12(high) M1 profile, whereas M-CSF+MCP-1 and FPR2 agonists skewed them into M2 (IL-10(high)IL-12(low)). In that respect, through modulating the phosphorylation of signal transducer and activator of transcription-3 (STAT3), LXA(4) and ANXA1 induced monocyte differentiation into M2a+M2c-like cells and showed antitumorigenetic activities, whereas SAA, LL-37 and M-CSF+MCP-1 led to M2b- or M2d-like polarization, which exacerbated HCC invasion in vitro and in vivo, respectively. Our results suggest that FPR2 has an appreciable pleiotropic regulator role in tumor immunoediting.