Harnessing the abscopal effect: mechanistic insights and therapeutic strategies for systemic cancer immunotherapy

The abscopal effect, defined as the regression of non-irradiated tumors following localized radiotherapy (RT), represents one of the most intriguing manifestations of systemic antitumor immunity. Although traditionally considered a rare and unpredictable phenomenon, increasing evidence indicates that the abscopal effect is an immune-mediated process initiated by RT-induced immunogenic cell death. In addition to directly eliminating tumor cells, RT promotes the release of tumor-associated antigens and danger-associated molecular patterns, activates antigen-presenting cells, and primes tumor-specific T-cell responses, thereby triggering systemic immune surveillance. The development of immunotherapy, particularly immune checkpoint inhibitors (ICIs), has substantially enhanced the likelihood of inducing abscopal responses by sustaining antitumor immunity and overcoming tumor-induced immune suppression. As a result, the abscopal effect has evolved from an anecdotal clinical observation into a promising strategy for systemic cancer treatment. However, its clinical application remains limited by tumor heterogeneity, the immunosuppressive tumor microenvironment, uncertainties regarding optimal radiation dose, fractionation, and treatment sequencing, as well as the lack of reliable predictive biomarkers. In this review, we summarize the current understanding of the biological mechanisms underlying the abscopal effect, discuss its reciprocal interaction with immunotherapy, and evaluate recent advances in radio-immunotherapy. We also highlight the major challenges that impede clinical translation and discuss future strategies for biomarker development, treatment optimization, and precision radio-immunotherapy. Overall, this review provides a comprehensive overview of the current landscape of the abscopal effect and offers perspectives on its development as a predictable and clinically applicable therapeutic strategy.