Stimulating Innate Immunity to Enhance Radiation Therapy–Induced Tumor Control

Novel ligands that target Toll-like receptors and other innate recognition pathways represent a potent strategy for modulating innate immunity to generate antitumor immunity. Although many of the current clinically successful immunotherapies target adaptive T-cell responses, both preclinical and clinical studies suggest that adjuvants have the potential to enhance the scope and efficacy of cancer immunotherapy. Radiation may be a particularly good partner to combine with innate immune therapies, because it is a highly efficient means to kill cancer cells but may fail to send the appropriate inflammatory signals needed to act as an efficient endogenous vaccine. This may explain why although radiation therapy is a highly used cancer treatment, true abscopal effects—regression of disease outside the field without additional systemic therapy—are extremely rare. This review focuses on efforts to combine innate immune stimuli as adjuvants with radiation, creating a distinct and complementary approach from T cell–targeted therapies to enhance antitumor immunity.