Implications of glioblastoma-derived exosomes in modifying the immune system: state-of-the-art and challenges.

Glioblastoma is a brain cancer with a poor prognosis. Failure of classical chemotherapy and surgical treatments indicates that new therapeutic approaches are needed. Among cell-free options, exosomes are versatile extracellular vesicles (EVs) that carry important cargo across barriers such as the blood-brain barrier (BBB) to their target cells. This makes exosomes an interesting option for the treatment of glioblastoma. Moreover, exosomes can comprise many therapeutic cargos, including lipids, proteins, and nucleic acids, sampled from special intercellular compartments of their origin cell. Cells exposed to various immunomodulatory stimuli can generate exosomes enriched in specific therapeutic molecules. Notably, the secretion of exosomes could modify the immune response in innate and adaptive immune systems. For instance, glioblastoma-associated exosomes (GBex) uptake by macrophages could influence macrophage dynamics (e.g., shifting CD markers expression). Expression of critical immunoregulatory proteins such as cytotoxic T-lymphocyte antigen-1 (CTLA1) and programmed death-1 (PD-1) on GBex indicates the direct crosstalk of these nano-size vesicles with the immune system. The present study reviews the role of exosomes in immune system cells, including B cells, T cells, natural killer (NK) cells, and dendritic cells (DCs), as well as novel technologies in the field.