Targeting the extracellular vesicle-immune axis in prostate cancer: mechanisms of immune evasion and emerging therapeutic strategies.

Prostate cancer is one of the least immunogenic malignancies and poorly responds to immunotherapies. Characterized by an immunosuppressive tumor microenvironment and a scarcity of cytotoxic T-cell infiltrates, prostate cancer has been closely linked to extracellular vesicles (EVs), including exosomes and microvesicles, as important immunomodulators of immune evasion, therapy resistance, and disease progression. Through their cargo of proteins, lipids, and nucleic acids, tumor-secreted EVs shape antigen presentation, immune checkpoint activity, myeloid cell fate, and pre-metastatic niche formation by exchanging programmed death-ligand 1 (PD-L1), cytokines, microRNAs (miRNAs), and other bioactive mediators. These discoveries have led to EVs being investigated not only as a mechanism for prostate cancer aggressiveness but also as therapeutic targets themselves. Furthermore, engineering EVs for cancer therapy has become more prominent over recent years, as they are used as natural delivery vehicles for immunomodulatory drugs, nucleic acids, and toxins, as well as for the development of cancer vaccines. In this review, we discuss the EV-immune axis in prostate cancer and how chemotherapeutics, EV biogenesis inhibitors, and radionuclides reprogram EV-immune interactions. Engineered EVs, dendritic cell-derived EVs, and EV vaccines are also explored as potential immunotherapeutic opportunities. Overall, by targeting EV-mediated signaling, one can tackle immune resistance from multiple angles and remodel the tumor microenvironment to respond to immunotherapies, such as immune checkpoint blockade.