Molecular mechanisms underlying the abscopal effect induced by radiotherapy and its synergistic translational potential with immunotherapy
Xinyi Chen, Mu Yang, Yongbiao Huang, Jingyao Tu, Yuwen Cai, Xianglin Yuan
Abstract
Abscopal immunity—the regression of distant, non-irradiated lesions after localized radiotherapy (RT)—signals conversion of focal DNA damage into systemic antitumor immunity. This review advances a unifying three-stage framework—initiation, amplification, and reinforcement—explaining how RT can be leveraged to elicit durable systemic control. In initiation, immunogenic cell death and cytosolic DNA activate cGAS–STING (with TLR3–interferon (IFN)-I as a compensatory axis), driving dendritic cell recruitment and cross-priming in tumor-draining lymph nodes. Amplification entails chemokine-guided trafficking and expansion of CXCR3 + cytotoxic T cells, together with stromal and vascular remodeling that enable infiltration at out-of-field sites. Reinforcement reflects the balance between memory formation and adaptive resistance (PD-L1 upregulation, myeloid/Treg accrual, adenosine, and metabolic checkpoints), defining actionable targets for combinatorial intervention. We critically appraise clinical data showing that RT paired with immune-checkpoint inhibition can increase out-of-field control in selected settings, whereas heterogeneous or negative trials underscore the importance of dose and fractionation, field design/target coverage, RT-immune checkpoint inhibitor sequencing, and sparing of lymphoid structures. We outline emerging levers—including spatially fractionated RT, FLASH RT, proton therapy, myeloid- and adenosine-axis blockade, and nanotechnology-enabled in situ vaccination—and candidate biomarkers (interferon-response signatures, circulating tumor DNA kinetics, T-cell clonotypes). Operationalizing these principles points toward making the abscopal effect a predictable, clinically actionable endpoint rather than a rarity.