Extracellular vesicles as missiles for enhanced anti-tumor efficacy of oncolytic viruses: from disseminating oncolysis and anti-tumor immunity to targeted delivery.

Oncolytic viruses (OVs) have been introduced as a promising anti-cancer platform capable of selectively killing cancer cells (oncolysis) without causing damage to normal cells. These viruses also stimulate the innate and adaptive immune responses and can remodel the tumor microenvironment (TME) in favor of anti-tumor immunity. Still, successful and efficient OV application in the clinical settings encounters several challenges including immune mediated clearance and low tumor tissue targeting. Extracellular vesicles (EVs) have emerged as a useful vehicle for efficient and selective delivery of various therapeutics including chemotherapy drugs, nucleic acid-based anti-cancer agents and immunostimulatory molecules into the TME. EVs can also be employed as a proper vehicle to enhance OVs tumor-selective delivery and protect them from the host immune system mediated removal following systemic administration as a key hurdle on the way of an efficacious oncolytic virotherapy. OVs can also take advantage of EVs to spread their oncolytic activity to metastatic sites distant from the primary tumor as well as instigate robust anti-tumor immune responses. In this paper, we have tried to review the current literature regarding the roles and applications of EVs in cancer OV therapy and provide a conclusion on future directions and application of this novel technology.