Exosomal POU5 F1 derived from TNBC promotes cancer progression by regulating M2 macrophage polarization via inhibiting TRAF6 ubiquitination and activating AKT in macrophage.

Abstract

Exosomes are pivotal in triple-negative breast cancer (TNBC) development, and accumulating evidence underscores their potential as therapeutic targets and diagnostic indicators. In this study, we revealed a significant enrichment of the POU domain, class 5, transcription factor 1 (POU5F1) in TNBC cells-derived exosomes. Functionally, silencing endogenous POU5F1 in TNBC cells substantially inhibited their aggressive phenotypes. Moreover, exosomes derived from TNBC cells contributed to macrophage M2 polarization by transferring POU5F1 to the recipient macrophages. Mechanistically, POU5F1 within these exosomes prevented the tumor necrosis factor receptor-associated factor 6 (TRAF6) degradation in macrophages, thereby activating the protein kinase B (AKT) signaling cascade and driving M2 polarization. Furthermore, in vivo experiments provided evidence that POU5F1 knockdown significantly reduced tumor growth and macrophage M2 polarization in a mouse model of TNBC cells by modulating the TRAF6/AKT signaling axis. Our study concludes that POU5F1 in TNBC cells-derived exosomes is vital for promoting macrophage M2 polarization by inhibiting TRAF6 ubiquitination and activating AKT signaling, thereby contributing to TNBC progression.