Abscopal Effect in Radiation Therapy: The Immune Mechanisms and Clinical Advances

The abscopal effect is a systemic antitumor response to localized radiotherapy (RT) that has emerged as a central focus in the era of immunotherapy. Clinical evidence demonstrates that local RT can induce regression of distant, nonirradiated metastases, including cases of complete remission. However, the effect remains unpredictable, with marked variation in clinical outcomes ranging from complete regression to paradoxical progression. The mechanistic basis for this heterogeneity and optimal strategies to enhance abscopal effects remain incompletely understood. This review synthesizes current evidence into a mechanistic framework organized around a three-stage immune cascade: ignition, orchestration, and execution. We examine how tumor-intrinsic factors, RT parameters, and biomarkers shape this cascade. We then appraise the clinical trial landscape and discuss how these mechanistic insights may inform patient selection, treatment timing, and radioimmunotherapy combination strategies. Critically, we establish a bidirectional framework distinguishing the favorable abscopal response from the pro-tumorigenic badscopal effect, in which RT paradoxically promotes distant progression through immunosuppressive pathways. By clarifying these mechanisms and variables, this review offers a framework for improving future clinical trial design and advancing the abscopal effect from a sporadically observed phenomenon to a predictable therapeutic strategy.