Modulating Purinergic Signaling to Improve Radiotherapy Outcomes

Over the past decades, the immunomodulatory properties of radiotherapy have started to be uncovered. This has prompted a new way of interpreting radiotherapy responses and opened novel avenues for combining radiotherapy with immunotherapy. A key component of radiation-induced immunogenicity is the extracellular release of danger-associated molecular patterns, including ATP and NAD. The presence of these purine metabolites in the extracellular space represents a potent signal of immune alert. However, the sensing and catabolism of extracellular ATP and NAD by purinergic receptors and ectonucleotidases, respectively, are perturbed in cancer, and the characterization of their effects on antitumor immune responses is a rapidly evolving research field. However, the impact of purinergic signalling on radiation-induced immune responses remains poorly understood. Here, we review the immunostimulatory and immunosuppressive processes induced by ATP and NAD in tumours, discuss their role in cancer radiotherapy, and opportunities for targeting them to improve responses in cancer patients.