Extracellular vesicles and the “six Rs” in radiotherapy

Over half of patients with cancer receive radiation therapy during the course of their disease. Decades of radiobiological research have identified 6 parameters affecting the biological response to radiation referred to as the 6 “Rs”: Repair, Radiosensitivity, Repopulation, Redistribution, Reoxygenation, and Reactivation of the anti-tumour immune response. Extracellular Vesicles (EVs) are small membrane-bound particles whose multiple biological functions are increasingly documented. Here we discuss the evidence for a role of EVs in the orchestration of the response of cancer cells to radiotherapy. We highlight that EVs are involved in DNA repair mechanisms, modulation of cellular sensitivity to radiation, and facilitation of tumour repopulation. Moreover, EVs influence tumour reoxygenation dynamics, and play a pivotal role in fostering radioresistance. Last, we examine how EV-related strategies could be translated into novel strategies aimed at enhancing the efficacy of radiation therapy against cancer.