Abstract

Monocyte-derived macrophages are usually recruited and play pivotal roles in establishing an immunosuppressive tumor microenvironment, and the interplay between tumor cells and tumor-associated macrophages (TAMs) is crucial for tumor development. However, the detailed mechanisms remain largely unelucidated in certain aggressive human cancers, such as melanoma. Here, through miRNA sequencing analysis, we found the microRNA miR-708-5p was highly enriched in melanoma exosomes, which was dependent on SFRS1. Treatment by melanoma exosomes facilitated M2 polarization of macrophages, while the polarized macrophages in turn promoted melanoma progression and metastasis both in vitro and in vivo. Mechanistically, miR-708-5p directly targets FOXN3, a member of the fork head/winged helix transcription factor family, and subsequently activates the PI3K/AKT/mTOR pathway in macrophages. Conversely, re-expression of FOXN3 in macrophages stably expressing miR-708-5p could reverse the impact on macrophages. In addition, downregulation of FOXN3 by miR-708-5p in macrophages reduced their phagocytic capacity and increased the secretion of IL-10 and TGF-β. Interestingly, we found that cellular retention of miR-708-5p could inhibit the proliferation and promote the apoptosis of melanoma cells, suggesting the necessity for secretion of this microRNA. In summary, our findings provide novel insights into the mechanism of melanoma-derived miR-708-5p in facilitating the formation of an immunosuppressive tumor microenvironment and indicate the potential of miR-708-5p and FOXN3 as therapeutic targets for the treatment of melanoma.