Facts and Hopes in Radioimmunotherapy for Localized Stages of Cancer

Radiotherapy (RT) has emerged as a promising partner to immunotherapy, owing to its capacity to induce immunogenic tumor cell death, modulate the tumor microenvironment, and prime systemic antitumor immunity. Preclinical studies demonstrate that focal RT elicits a variety of immunologic effects, recruiting both the innate and adaptive immune system, that enable it to function as an in situ vaccine. Translational work has underscored the relevance of RT fractionation, timing, and field choice to enhance synergy with immune checkpoint inhibitors. In this review, we examine the clinical rationale and translational progress underpinning RT-immunotherapy combinations in the localized, nonmetastatic setting of cancer. We summarize the results of pivotal trials that have tested the immunogenic use of RT across multiple disease sites in combination with immune checkpoint inhibitors and propose interpretations for the results of these trials. Finally, we highlight emerging opportunities to optimize radiation-immunotherapy through rational treatment sequencing, the choice of the immunotherapy partner for combinations, and the emerging development of a biomarker-informed patient selection. We conclude by emphasizing the importance of better understanding, in human specimens, how irradiated cancers and normal tissues shape local and systemic immune responses to inform a more rational design of the next generation of RT-immunotherapy clinical trials.