Extracellular vesicles in the immune regulation of hematological malignancies: mechanisms, prognostic significance, and therapeutic opportunities

Abstract

The progressive cross-talk between tumor cells and the immune microenvironment, which is required for tumor growth, progression, and dissemination, has been well documented in solid cancers and is increasingly recognized in hematological malignancies. Extracellular vesicles (EVs) are now emerging as essential facilitators of immune-tumor crosstalk. In hematological cancers, EVs from leukemia, lymphoma, and myeloma cells carry oncogenic proteins, lipids, cytokines, and non-coding RNAs that reprogram immune cells and establish tumor-promoting immune states, in which tumor cells are protected from immune elimination and therapy-induced cell death. Evidence shows that tumor-derived EVs impair antitumor immunity, in part, by promoting macrophage M2 polarization, myeloid-derived suppressor cell (MDSC) expansion, dendritic cell maturation, T-cell exhaustion, and NK-cell cytotoxicity. Tumor cell-derived EV cargo, such as PD-L1, TGF-β, IL-10, and tumor-encoded miRNAs, creates highly immunosuppressive niches that promote disease progression and are associated with a dismal prognosis. On the other hand, immune-cell–derived or engineered EVs can activate CD4 + and CD8 + T cells, augment NK-cell killing, and serve as highly potent vehicles for antigen delivery or immune checkpoint modulation. By modifying the EV cargo, blocking EV uptake, or using EVs as vaccines or targeted delivery vehicles, it is now possible to restore antitumor immunity and reverse immunotherapy resistance. This review will provide an update on the current understanding of EVs in the regulation of hematological cancers, from mechanistic, translational, and therapeutic perspectives. We will also discuss the potential of using EVs as biomarkers and as next-generation immunotherapeutic agents.