Radiation as an immune modulator: mechanisms and implications for combination with immunotherapy

Radiation therapy can directly kill cancer cells, while simultaneously modulating the immune response. The advent of immune checkpoint blockade (ICB) provided compelling rationale for combination with radiation therapy to improve systemic tumour control. Although this strategy has improved survival in specific contexts, including cervical cancer and head and neck squamous cell carcinoma, the majority of combination trials have not demonstrated clinical benefit and predictive biomarkers remain elusive. These heterogeneous outcomes reflect fundamental gaps in understanding how radiation parameters influence immunological responses. Technological advances enabling diverse radiation delivery protocols have revealed that dose and fractionation profoundly impact the balance between immunostimulation and immunosuppression. Emerging evidence indicates that radiation protocols optimized for cytotoxic effects may not be optimal for immunological synergy with ICB. In this Review, we examine how radiation dose, fractionation and treatment volume shape local and systemic immunity, reconciling mechanistic insights with divergent clinical trial outcomes. We provide rationale for transitioning from empirical combinations towards immunologically informed radiation protocols that could help realize the full potential of radioimmunotherapy combinations. Radiation therapy induces immune responses both systemically and within the tumour microenvironment. In this Review, Darragh and Karam present preclinical and clinical evidence to highlight this complex interplay and outline strategies to enhance the immunogenic potential of radiation therapy to improve both therapeutic efficacy and patient outcomes.