Revisiting the Abscopal Effect in the Era of Immuno-Radiotherapy: Mechanisms, Challenges, and Clinical Perspectives

Background: The abscopal effect refers to the clinical response of non-irradiated tumor lesions following localized radiotherapy (RT). Once regarded as a rare phenomenon, it has gained renewed interest in the era of immunotherapy, as RT may promote systemic anti-tumor immune responses. This narrative review summarizes current biological, radiobiological, and clinical evidence on the abscopal effect and highlights translational gaps limiting its reproducibility. Methods: Preclinical, translational, and clinical evidence was qualitatively analyzed across seven domains: RT, immunology, and clinical oncology. A structured qualitative gap analysis was used to identify disconnections between biological mechanisms, RT parameters, biomarkers, and clinical outcomes. Results: Current evidence supports the biological plausibility of the abscopal effect through immunogenic cell death, antigen and damage-associated molecular patterns (DAMP) release, activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, dendritic-cell priming, and T-cell-mediated responses. However, clinical results remain heterogeneous. Dose, fractionation, irradiated volume, timing, lymphocyte preservation, and interventional RT (modern brachytherapy, IRT) may influence systemic immune activation. Emerging biomarkers, particularly extracellular vesicles (EVs), may help connect radiation-induced biological stress with immune modulation and clinical response. Conclusions: The main barrier to clinical translation is the fragmentation of evidence across RT, immunology, and clinical oncology. Integrated translational frameworks combining dosimetry, immune monitoring, EVs-based biomarkers, imaging, and clinical endpoints may improve the interpretation and reproducibility of abscopal responses in immuno-RT.