Leveraging the immunomodulatory effects of radiation therapy (RT) for synergy with immunotherapeutic agents for the treatment of cancer is an area of immense interest. A pressing deficiency in the translation of this strategy into the clinic is the lack of clarity on the impact of radiation dose-fractionation on host anti-cancer immune defences. Using a series of rationally selected radiation schedules in mouse models of solid cancer, we demonstrated that radiation dose per fraction and total dose can independently and differentially shape anti-tumor immune responses and their interplay with immune checkpoint blockade (ICB) therapy. In this commentary, we extend our discussions on the complex and far-reaching impact of radiation dose-fractionation on the tumor immune microenvironment and the therapeutic implications thereof. We also outline the nuances in examining this question and focus on the clinical translatability of our current body of knowledge to re-evaluate RT and ICB combination strategies in the clinic.

Radiation therapy, Radiation dose-fractionation, Immune checkpoint blockade therapy, Innate and adaptive anti-cancer immune responses, T regulatory cells (Tregs), Immunosuppression, Preclinical models of solid cancer, Immuno-oncology