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This review advances a unifying three-stage framework\u2014initiation, amplification, and reinforcement\u2014explaining how RT can be leveraged to elicit durable systemic control. In initiation, immunogenic cell death and cytosolic DNA activate cGAS\u2013STING (with TLR3\u2013interferon (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\n                    <jats:sup>+<\/jats:sup>\n                    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\u2014including spatially fractionated RT, FLASH RT, proton therapy, myeloid- and adenosine-axis blockade, and nanotechnology-enabled in situ vaccination\u2014and 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.\n                  <\/jats:p>","DOI":"10.1177\/17588359251387534","type":"journal-article","created":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T11:21:20Z","timestamp":1761909680000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":33,"title":["Molecular mechanisms underlying the abscopal effect induced by radiotherapy and its synergistic translational potential with immunotherapy"],"prefix":"10.1177","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0638-1380","authenticated-orcid":false,"given":"Xinyi","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mu","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongbiao","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyao","family":"Tu","sequence":"additional","affiliation":[{"name":"Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuwen","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Wuhan Children\u2019s Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 100, Xianggang Road, Jiang\u2019an District, Wuhan, Hubei Province, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4653-5388","authenticated-orcid":false,"given":"Xianglin","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2025,10,31]]},"reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc.2018.6"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.currproblcancer.2015.10.001"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1259\/bjr.20200042"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-22-0516"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.4161\/onci.28780"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.adro.2022.100909"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2020.106663"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.medj.2023.02.003"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms15618"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2017.1339857"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-14-1258"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2015.1016709"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.32934"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13014-018-1049-3"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.5230\/jgc.2021.21.e24"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10143-025-03505-1"},{"issue":"8","key":"e_1_3_4_18_2","article-title":"Stereotactic body radiation therapy and thymosin alpha-1-induced anti-tumor effects in heavily pretreated, metastatic esophageal squamous cell carcinoma patients","volume":"7","author":"Du D","year":"2018","unstructured":"Du D, Song T, Dai H, et al. 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