Abstract
Extracellular vesicles (EVs) are important mediators of intercellular communication in the tumour microenvironment. The cytokine transforming growth factor-β (TGF-β) facilitates cancer progression via EVs secreted by cancer cells, which act on recipient cells in the tumour microenvironment. However, the mechanisms of how TGF-β affects cancer cell EV release and composition are incompletely understood. Here, we systematically investigate the effects of TGF-β on the release and protein composition of EVs from breast cancer cells. TGF-β suppresses the transcription of RAB27B mediated by SMAD3 and thereby hampers EV release. Using click chemistry and quantitative proteomics, we found that TGF-β increases the quantity of protein cargo and changes the composition of EVs by downregulating RAB27B expression. The recomposed EVs, induced by TGF-β or RAB27B depletion, inhibit CD8+ T cell-mediated breast cancer killing. Our findings reveal the critical roles of TGF-β and RAB27B in cancer development by regulating EV release and composition and thus provide potential targets to improve cancer immunotherapy.