Prostate cancer cell-derived exosomes inhibit macrophage phagocytosis through EIF3B-mediated exosomal sorting of miR-100-5p.

Exosomes play significant roles in the tumor microenvironment (TME). In particular, some exosomal microRNAs (miRNAs) have the ability to mediate macrophage polarization. However, the mechanism underlying the selective enrichment of miRNAs into exosomes remains largely unknown. Herein, we compared the expression of miR-100-5p in exosomes derived from normal prostate epithelial cells and PC-3 cells. Subsequently, macrophages were treated with the aforementioned exosomes separately. Our results demonstrate that prostate cancer (PC)-derived exosomes can transfer miRNA-100-5p to macrophages and significantly increase miR-100-5p expression. To explore the role and mechanisms of exosomal miR-100-5p in macrophages, we performed phagocytosis assay and reactive oxygen species (ROS) detection experiment. Knockdown of miR-100-5p markedly promoted ROS generation in macrophages induced with PC-3 exosomes through the NADPH oxidase 4 (NOX4) pathway, leading to the increased phagocytosis of macrophages. Importantly, our results confirmed that eukaryotic translation initiation factor 3 subunit B (EIF3B) was highly expressed in PC cells and specifically bound to miR-100-5p by pull-down assay, and EIF3B knockdown decreased the enrichment of miR-100-5p in PC-3 exosomes. Collectively, our data showed that EIF3B-mediated selective sorting of miR-100-5p into PC exosomes reduced the generation of ROS by targeting NOX4 in macrophages, thus inhibiting macrophage phagocytosis. These findings reveal a new role for EIF3B in regulating the sorting of miR-100-5p into PC-3-derived exosomes, and identify an important new mode of TME regulation.