Cancer stem cell-derived exosomes in CD8+ T cell exhaustion

•In this review article, I propose the following.•CSC-derived exosomes express PD-L1 and upregulate PD-1 expression on CD8+ T cells.•CSC-derived exosomal TGF-β modulates mTOR in CD8+ T cells.•CSC-derived exosomes induce HIF-1α to promote glycolysis in CD8+ T cells.•CSC-derived exosomal Notch1 amplifies CSC enrichment and CD8+ T cell exhaustion. Tumor-derived extracellular vesicles (EVs) are one of the most important ways of intercellular communication and signaling. Cancer stem cells (CSCs) secrete EVs to modulate immune checkpoint molecules and evade immune surveillance. Activated CD8+ T cells known as cytotoxic T lymphocytes (CTLs) are the most powerful anti-cancer adaptive cells. Their activity is compromised upon encountering cells and signaling within the tumor microenvironment (TME), resulting in hyporesponsiveness called exhaustion. CSC-derived exosomes express programmed death ligand-1 (PD-L1) and upregulate programmed death-1 (PD-1) on CD8+ T cells to promote their exhaustion. PD-L1 expression on tumor-derived exosomes appears to be induced by CSC-derived exosomes containing transforming growth factor (TGF)-β. Tenascin-C is another constituent of CSC exosomes that acts on mammalian target of rapamycin (mTOR) signaling in T cells. Glycolysis is a metabolic event promoted by the inducing effect of CSC-derived exosomes on hypoxia-inducible factor-1α (HIF-1α). CSC interaction with CD8+ T cells is even more complex as the CSC-derived exosomes contain Notch1 to stimulate stemness in non-tumor cells, and the inducible effect of Notch1 on PD-1 promotes CD8+ T cell exhaustion. CSC exosome targeting has not been extensively studied yet. Advances in the field will open up new therapeutic windows and shape the future of cancer immunotherapy.