Safety of combining radiotherapy with immune-checkpoint inhibition

Immune-checkpoint inhibitors targeting cytotoxic T- lymphocyte antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), or programmed cell death 1 ligand 1 (PD-L1) have transformed the care of patients with a wide range of advanced-stage malignancies. More than half of these patients will also have an indication for treatment with radiotherapy. The effects of both radiotherapy and immune-checkpoint inhibition (ICI) involve a complex interplay with the innate and adaptive immune systems, and accumulating evidence suggests that, under certain circumstances, the effects of radiotherapy synergize with those of ICI to augment the antitumour responses typically observed with either modality alone and thus improve clinical outcomes. However, the mechanisms by which radiotherapy and immune-checkpoint inhibitors synergistically modulate the immune response might also affect both the type and severity of treatment-related toxicities. Moreover, in patients receiving immune-checkpoint inhibitors, the development of immune-related adverse events has been linked with superior treatment responses and patient survival durations, suggesting a relationship between the antitumour and adverse autoimmune effects of these agents. In this Review, we discuss the emerging data on toxicity profiles related to immune-checkpoint inhibitors and radiotherapy, both separately and in combination, their potential mechanisms, and the approaches to managing these toxicities.