The Immunomodulatory Role of Hypoxic Tumor-Derived Extracellular Vesicles

Simple Summary Hypoxia, a characteristic of many cancer types, can suppress the antitumor effector functions of the adaptive and innate immune system. Tumor-cell-derived extracellular vesicles, which function as a mechanism of communication between tumor cells and immune cells, are also affected by hypoxia, and may drive immunosuppression. The aim of this review is to summarize the current knowledge on hypoxic cancer-cell-derived extracellular vesicles in immunosuppression, and to provide an overview of enriched factors (i.e., miRNA and proteins) in hypoxic tumor-derived EVs and their role in immunomodulation. This complete overview may indicate relevant directions for future research into the role of hypoxia in immunosuppression during cancer. Tumor-associated immune cells frequently display tumor-supportive phenotypes. These phenotypes, induced by the tumor microenvironment (TME), are described for both the adaptive and the innate arms of the immune system. Furthermore, they occur at all stages of immune cell development, up to effector function. One major factor that contributes to the immunosuppressive nature of the TME is hypoxia. In addition to directly inhibiting immune cell function, hypoxia affects intercellular crosstalk between tumor cells and immune cells. Extracellular vesicles (EVs) play an important role in this intercellular crosstalk, and changes in both the number and content of hypoxic cancer-cell-derived EVs are linked to the transfer of hypoxia tolerance. Here, we review the current knowledge about the role of these hypoxic cancer-cell-derived EVs in immunosuppression. In addition, we provide an overview of hypoxia-induced factors (i.e., miRNA and proteins) in tumor-derived EVs, and their role in immunomodulation.