Molecular mechanisms underlying the abscopal effect induced by radiotherapy and its synergistic translational potential with immunotherapy

作者：Xinyi Chen, Mu Yang, Yongbiao Huang, Jingyao Tu, Yuwen Cai, Xianglin Yuan · 发表于：Therapeutic Advances in Medical Oncology · 年份：2025 · DOI：10.1177/17588359251387534 · 被引用次数：19 · 研究领域：Cancer Immunotherapy and Biomarkers、interferon and immune responses、Colorectal and Anal Carcinomas

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 vaccinati...