{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T15:46:41Z","timestamp":1784735201128,"version":"3.55.0"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T00:00:00Z","timestamp":1768867200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Public Health"],"abstract":"<jats:p>\n                    Proton beam therapy is widely regarded for its cost-effectiveness, precision, and protection of normal tissues. Emerging evidence shows that conventional radiotherapy can inhibit primary tumors and promote immunogenicity of distant tumors, possibly via damage-associated molecular patterns (DAMPs) like calreticulin (CRT) and high mobility group box 1 (HMGB1) released during immunogenic cell death (ICD). However, the role of proton beams in inducing DAMPs and enhancing immunogenicity remains unclear. This study aimed to investigate the effects of proton beam-induced DAMPs on the colonization of distal tumors. In this study,\n                    <jats:italic>in vitro<\/jats:italic>\n                    cell irradiation experiments were conducted to identify the optimal proton beam dose for enhancing DAMPs expression in mouse colon carcinoma Colon-26 cells. Based on the optimal proton dose determined\n                    <jats:italic>in vitro<\/jats:italic>\n                    , a tumor-bearing mouse model was employed to evaluate its efficacy in inhibiting distal tumor colonization. To explore the mechanisms behind the anti-tumor effects, shRNA targeting DAMPs-related immunogenic molecules was applied to assess the immune response.\n                    <jats:italic>In vitro<\/jats:italic>\n                    findings indicated high-dose proton irradiation markedly induces HMGB1 release yet exerts no significant effect on CRT membrane exposure. Following high-dose proton beam irradiation, tumor cells transfected with shRNA exhibited a significant reduction in CRT and HMGB1 expression compared with the con-shRNA-irradiated control group.\n                    <jats:italic>In vivo<\/jats:italic>\n                    experiments demonstrated that HMGB1 knockdown reduced distal-tumor rejection by 60%, whereas CRT knockdown reduced it by only 20%, indicating that HMGB1 release may dominate proton-induced ICD. Our research results indicated that high-dose proton irradiation trigger the rejection of distal tumor colonization through a signaling pathway that depends on HMGB1. This research advanced our understanding of proton beam therapy immunological mechanisms and offered insights for improving tumor treatment outcomes.\n                  <\/jats:p>","DOI":"10.3389\/fpubh.2025.1686678","type":"journal-article","created":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T14:42:17Z","timestamp":1768920137000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Proton beam therapy induces protective immunity via HMGB1-dependent signaling"],"prefix":"10.3389","volume":"13","author":[{"given":"Jialing","family":"Wen","sequence":"first","affiliation":[{"name":"Department of Nuclear Physics, China Institute of Atomic Energy","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuanzhang","family":"Tu","sequence":"additional","affiliation":[{"name":"Department of Nuclear Physics, China Institute of Atomic Energy","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wangcai","family":"Ren","sequence":"additional","affiliation":[{"name":"College of Physics and Optoelectronic Engineering, Shenzhen University","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiaojuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Nuclear Physics, China Institute of Atomic Energy","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Nuclear Physics, China Institute of Atomic Energy","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Nuclear Physics, China Institute of Atomic Energy","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kensuke","family":"Osada","sequence":"additional","affiliation":[{"name":"Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology (QST)","place":["Chiba, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Shimokawa","sequence":"additional","affiliation":[{"name":"Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology (QST)","place":["Chiba, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihisa","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Gunma University Heavy Ion Medical Center","place":["Maebashi, Gunma, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nakako Izumi","family":"Nakajima","sequence":"additional","affiliation":[{"name":"QST Hospital, National Institutes for Quantum Science and Technology (QST)","place":["Chiba, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shenke","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University","place":["Zhengzhou, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenchao","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Artificial Intelligence Medicine, Graduate School of Medicine, Chiba University","place":["Chiba, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Harbin Medical University Cancer Hospital","place":["Harbin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Li","sequence":"additional","affiliation":[{"name":"China CDC Key Laboratory of Radiological Protection and Nuclear Emergency, National Institute for Radiological Protection, Chinese Center for Disease Control and Prevention","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Sui","sequence":"additional","affiliation":[{"name":"Department of Nuclear Physics, China Institute of Atomic Energy","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liqiu","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Nuclear Physics, China Institute of Atomic Energy","place":["Beijing, China"]},{"name":"Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology (QST)","place":["Chiba, Japan"]},{"name":"Gunma University Heavy Ion Medical Center","place":["Maebashi, Gunma, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,20]]},"reference":[{"key":"ref1","year":""},{"key":"ref2","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1038\/s41392-024-01885-2","article-title":"Mechanism insights and therapeutic intervention of tumor metastasis: latest developments and perspectives","volume":"9","author":"Shi","year":"2024","journal-title":"Signal Transduct Target Ther"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"1519","DOI":"10.1038\/s41467-024-45307-x","article-title":"Causes of death among people living with metastatic Cancer","volume":"15","author":"Mani","year":"2024","journal-title":"Nat Commun"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1038\/nrc865","article-title":"Dissemination and growth of Cancer cells in metastatic sites","volume":"2","author":"Chambers","year":"2002","journal-title":"Nat Rev Cancer"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1186\/s43556-025-00261-y","article-title":"Cancer metastasis: molecular mechanisms and therapeutic interventions","volume":"6","author":"Dai","year":"2025","journal-title":"Molecular biomedicine"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1038\/s41392-025-02148-4","article-title":"Invasion and metastasis in cancer: molecular insights and therapeutic targets","volume":"10","author":"Li","year":"2025","journal-title":"Signal Transduct Target Ther"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"20190226","DOI":"10.1259\/bjr.20190226","article-title":"Proton beam therapy for tumors of the upper abdomen","volume":"93","author":"Raldow","year":"2020","journal-title":"Br J Radiol"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1002\/pro6.1149","article-title":"A review of proton therapy - current status and future directions","volume":"6","author":"Mohan","year":"2022","journal-title":"Precis Radiat Oncol"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"4545","DOI":"10.3390\/cancers13184545","article-title":"Dosimetry, efficacy, safety, and cost-effectiveness of proton therapy for non-small cell lung cancer","volume":"13","author":"Qiu","year":"2021","journal-title":"Cancers"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1186\/s40880-019-0407-3","article-title":"New Frontiers in proton therapy: applications in cancers","volume":"39","author":"Yuan","year":"2019","journal-title":"Cancer Commun"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/j.semradonc.2017.08.004","article-title":"Proton therapy for head and neck cancers","volume":"28","author":"Blanchard","year":"2018","journal-title":"Semin Radiat Oncol"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1016\/j.ijrobp.2015.01.005","article-title":"Early toxicity in patients treated with postoperative proton therapy for locally advanced breast cancer","volume":"92","author":"Cuaron","year":"2015","journal-title":"Int J Radiat Oncol Biol Phys"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1186\/1748-717x-8-144","article-title":"An in-silico comparison of proton beam and Imrt for postoperative radiotherapy in completely resected stage Iiia non-small cell lung cancer","volume":"8","author":"Berman","year":"2013","journal-title":"Radiat Oncol"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"460","DOI":"10.1016\/j.ijrobp.2009.02.030","article-title":"Proton beam therapy for large hepatocellular carcinoma","volume":"76","author":"Sugahara","year":"2010","journal-title":"Int J Radiat Oncol Biol Phys"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"e70003","DOI":"10.1002\/cai2.70003","article-title":"Immunological effects of proton radiotherapy: new opportunities and challenges in cancer therapy","volume":"4","author":"Zhang","year":"2025","journal-title":"Cancer innovation"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"228","DOI":"10.3390\/cells10020228","article-title":"The potentiation of anti-tumor immunity by tumor abolition with alpha particles, protons, or carbon ion radiation and its enforcement by combination with Immunoadjuvants or inhibitors of immune suppressor cells and checkpoint molecules","volume":"10","author":"Keisari","year":"2021","journal-title":"Cells"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1016\/j.ijrobp.2016.02.022","article-title":"Tumor cells surviving exposure to proton or photon radiation share a common immunogenic modulation signature, rendering them more sensitive to T cell-mediated killing","volume":"95","author":"Gameiro","year":"2016","journal-title":"Int J Radiat Oncol Biol Phys"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"1765","DOI":"10.2174\/1381612023394089","article-title":"Immune modulation by ionizing radiation and its implications for Cancer immunotherapy","volume":"8","author":"Friedman","year":"2002","journal-title":"Curr Pharm Des"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"542","DOI":"10.21037\/atm.2019.09.128","article-title":"Comparison of the effects of photon, proton and carbon-ion radiation on the Ecto-Calreticulin exposure in various tumor cell lines","volume":"7","author":"Huang","year":"2019","journal-title":"Ann Transl Med"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"e631","DOI":"10.1038\/cddis.2013.156","article-title":"Many faces of Damps in Cancer therapy","volume":"4","author":"Krysko","year":"2013","journal-title":"Cell Death Dis"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"e0307024","DOI":"10.1371\/journal.pone.0307024","article-title":"High-dose radiation-induced immunogenic cell death of bladder Cancer cells leads to dendritic cell activation","volume":"19","author":"Zeng","year":"2024","journal-title":"PLoS One"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"2315","DOI":"10.1038\/nprot.2006.339","article-title":"Clonogenic assay of cells in vitro","volume":"1","author":"Franken","year":"2006","journal-title":"Nat Protoc"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"705361","DOI":"10.3389\/fimmu.2021.705361","article-title":"Immunogenic cell death induction by ionizing radiation","volume":"12","author":"Zhu","year":"2021","journal-title":"Front Immunol"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"1848","DOI":"10.1038\/sj.cdd.4402201","article-title":"Calreticulin exposure is required for the immunogenicity of gamma-irradiation and Uvc light-induced apoptosis","volume":"14","author":"Obeid","year":"2007","journal-title":"Cell Death Differ"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"e000337","DOI":"10.1136\/jitc-2019-000337","article-title":"Consensus guidelines for the definition, detection and interpretation of immunogenic cell death","volume":"8","author":"Galluzzi","year":"2020","journal-title":"J Immunother Cancer"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"102926","DOI":"10.1016\/j.arr.2025.102926","article-title":"Redox-sensitive high mobility group box 1 (Hmgb1) is a multifunctional regulator of cellular senescence, inflammation, and immunosuppression: impact on the aging process","volume":"113","author":"Salminen","year":"2026","journal-title":"Ageing Res Rev"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1146\/annurev-immunol-032712-100008","article-title":"Immunogenic cell death in Cancer therapy","volume":"31","author":"Kroemer","year":"2013","journal-title":"Annu Rev Immunol"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"8151","DOI":"10.3390\/ijms21218151","article-title":"Immunomodulatory effects of radiotherapy","volume":"21","author":"Kumari","year":"2020","journal-title":"Int J Mol Sci"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1111\/j.1600-065X.2007.00574.x","article-title":"High-mobility group box 1 (Hmgb1) protein at the crossroads between innate and adaptive immunity","volume":"220","author":"Bianchi","year":"2007","journal-title":"Immunol Rev"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1189\/jlb.0306171","article-title":"The secretion of Hmgb1 is required for the migration of maturing dendritic cells","volume":"81","author":"Dumitriu","year":"2007","journal-title":"J Leukoc Biol"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"825","DOI":"10.1038\/sj.embor.7400205","article-title":"Hmgb1 is an endogenous immune adjuvant released by necrotic cells","volume":"5","author":"Rovere-Querini","year":"2004","journal-title":"EMBO Rep"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1111\/imr.12573","article-title":"Abscopal, immunological effects of radiotherapy: narrowing the gap between clinical and preclinical experiences","volume":"280","author":"Brix","year":"2017","journal-title":"Immunol Rev"}],"container-title":["Frontiers in Public Health"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpubh.2025.1686678\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T07:38:35Z","timestamp":1771918715000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpubh.2025.1686678\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,20]]},"references-count":32,"alternative-id":["10.3389\/fpubh.2025.1686678"],"URL":"https:\/\/doi.org\/10.3389\/fpubh.2025.1686678","relation":{},"ISSN":["2296-2565"],"issn-type":[{"value":"2296-2565","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,20]]},"article-number":"1686678"}}