{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T06:00:10Z","timestamp":1785218410974,"version":"3.55.0"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T00:00:00Z","timestamp":1785196800000},"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. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Triple-negative breast cancer (TNBC) is a highly aggressive subtype characterized by significant inter- and intra-tumoral heterogeneity. Its varied response to radiotherapy limits clinical outcomes, yet the underlying molecular determinants remain poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      By integrating single-cell and bulk transcriptomic data, we profiled cell-type-specific radiosensitivity and defined distinct molecular subtypes via consensus clustering. A random survival forest (RSF) prognostic model was then constructed using 34 survival-associated genes and interpreted via SHAP analysis, and its performance was validated in multiple independent external cohorts. RAD51 was prioritized via Dependency Map (DepMap) analysis, and its functional role was validated\n                      <jats:italic>in vitro<\/jats:italic>\n                      and\n                      <jats:italic>in vivo<\/jats:italic>\n                      , supporting its role as a biological dependency in radiotherapy response. Moreover, tumor immune remodeling was further evaluated by immunofluorescence and protein analysis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Single-cell analysis revealed that fibroblasts, macrophages, and proliferative cells harbored elevated radioresistance signatures compared to lymphoid lineages. Bulk profiling identified two distinct subtypes: Cluster A (immunosuppressive, radioresistant, poor prognosis) and Cluster B (immune-active, favorable survival). The RSF model robustly stratified patient risk, with high-risk tumors tightly linked to an immune-desert microenvironment. DepMap analysis nominated RAD51 as a core biological dependency. Importantly, RAD51 knockdown sensitized TNBC cells to irradiation by exacerbating DNA damage, triggering G2\/M phase arrest, and driving apoptosis. Consistently,\n                      <jats:italic>in vivo<\/jats:italic>\n                      RAD51 silencing synergized with radiotherapy to significantly suppress tumor growth. Notably, this combination reshaped the immunosuppressive TME, driving robust CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell infiltration, M1 macrophage repolarization, and adaptive PD-L1 upregulation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This integrative multi-omics study delineates the cellular and molecular landscape of TNBC radioresistance. The RSF model provides a robust tool for risk stratification, while identifying RAD51 as a potential therapeutic target to restore radiosensitivity and reverse immunosuppression, particularly in high-risk, immune-cold tumors.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1866358","type":"journal-article","created":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T05:35:08Z","timestamp":1785216908000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Risk stratification and multi-omics reveal RAD51 inhibition as a radiosensitizing strategy in triple-negative breast cancer"],"prefix":"10.3389","volume":"17","author":[{"given":"Ran","family":"An","sequence":"first","affiliation":[{"name":"Department of Breast Imaging, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer","place":["Tianjin, China"]},{"name":"Tianjin Medical University Cancer Institute & Hospital, Tianjin\u2019s Clinical Research Center for Cancer","place":["Tianjin, China"]},{"name":"Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education","place":["Tianjin, China"]},{"name":"Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Cancer Prevention and Therapy","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianming","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Breast Imaging, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer","place":["Tianjin, China"]},{"name":"Tianjin Medical University Cancer Institute & Hospital, Tianjin\u2019s Clinical Research Center for Cancer","place":["Tianjin, China"]},{"name":"Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education","place":["Tianjin, China"]},{"name":"Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Cancer Prevention and Therapy","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianhui","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Breast Imaging, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer","place":["Tianjin, China"]},{"name":"Tianjin Medical University Cancer Institute & Hospital, Tianjin\u2019s Clinical Research Center for Cancer","place":["Tianjin, China"]},{"name":"Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education","place":["Tianjin, China"]},{"name":"Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Cancer Prevention and Therapy","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cunyu","family":"Tang","sequence":"additional","affiliation":[{"name":"Tianjin Medical University Cancer Institute & Hospital, Tianjin\u2019s Clinical Research Center for Cancer","place":["Tianjin, China"]},{"name":"Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Cancer Prevention and Therapy","place":["Tianjin, China"]},{"name":"Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Breast Imaging, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer","place":["Tianjin, China"]},{"name":"Tianjin Medical University Cancer Institute & Hospital, Tianjin\u2019s Clinical Research Center for Cancer","place":["Tianjin, China"]},{"name":"Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education","place":["Tianjin, China"]},{"name":"Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Cancer Prevention and Therapy","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: Globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA: A Cancer J For Clin"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14102569","article-title":"Breast cancer-epidemiology, classification, pathogenesis and treatment (review of literature)","volume":"14","author":"Smolarz","year":"2022","journal-title":"Cancers"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(20)32381-3","article-title":"Breast cancer","volume":"397","author":"Loibl","year":"2021","journal-title":"Lancet (London England)"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdt303","article-title":"Personalizing the treatment of women with early breast cancer: Highlights of the St Gallen International Expert Consensus on the primary therapy of early breast cancer 2013","volume":"24","author":"Goldhirsch","year":"2013","journal-title":"Ann Oncol Off J Eur Soc For Med Oncol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(16)32454-0","article-title":"Molecular alterations in triple-negative breast cancer-the road to new treatment strategies","volume":"389","author":"Denkert","year":"2017","journal-title":"Lancet (London England)"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.Cd-18-1177","article-title":"Insights into molecular classifications of triple-negative breast cancer: Improving patient selection for treatment","volume":"9","author":"Garrido-Castro","year":"2019","journal-title":"Cancer Discov"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.22836","article-title":"Differences in breast carcinoma characteristics in newly diagnosed African-American and Caucasian patients: A single-institution compilation compared with the National Cancer Institute's Surveillance, Epidemiology, and End Results database","volume":"110","author":"Morris","year":"2007","journal-title":"Cancer"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.Ccr-06-3045","article-title":"Triple-negative breast cancer: Clinical features and patterns of recurrence","volume":"13","author":"Dent","year":"2007","journal-title":"Clin Cancer Res: Off J Am Assoc For Cancer Res"},{"key":"B9","article-title":"Gstp 1 expression predicts poor pathological complete response to neoadjuvant chemotherapy in Er\u2010negative breast cancer","volume":"103","author":"Miyake","year":"2012"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.canrad.2023.07.005","article-title":"Breast cancer radiation therapy: Current questions in 2023","volume":"27","author":"Bollet","year":"2023","journal-title":"Cancer Radiotherapie: J la Societe Francaise Radiotherapie Oncologique"},{"key":"B11","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1038\/s41571-022-00709-y","article-title":"Predicting tumour radiosensitivity to deliver precision radiotherapy","volume":"20","author":"Price","year":"2023","journal-title":"Nat Rev Clin Oncol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1991","DOI":"10.1016\/s0140-6736(23)01082-6","article-title":"Radiotherapy to regional nodes in early breast cancer: An individual patient data meta-analysis of 14 324 women in 16 trials","volume":"402","author":"Taylor","year":"2023","journal-title":"Lancet (London England)"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/s1470-2045(14)71104-0","article-title":"Radiation therapy in the locoregional treatment of triple-negative breast cancer","volume":"16","author":"Moran","year":"2015","journal-title":"Lancet Oncol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.ctrv.2016.05.001","article-title":"The value of adjuvant radiotherapy on survival and recurrence in triple-negative breast cancer: A systematic review and meta-analysis of 5507 patients","volume":"47","author":"O'Rorke","year":"2016","journal-title":"Cancer Treat Rev"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2007.14.5565","article-title":"Estrogen receptor, progesterone receptor, Her-2, and response to postmastectomy radiotherapy in high-risk breast cancer: The Danish Breast Cancer Cooperative Group","volume":"26","author":"Kyndi","year":"2008","journal-title":"J Clin Oncol Off J Am Soc Clin Oncol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2020.03.007","article-title":"Intratumor heterogeneity: The Rosetta stone of therapy resistance","volume":"37","author":"Marusyk","year":"2020","journal-title":"Cancer Cell"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.breast.2017.07.004","article-title":"Risk of secondary Malignancies after radiation therapy for breast cancer: Comprehensive results","volume":"35","author":"Burt","year":"2017","journal-title":"Breast"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2017.72.7263","article-title":"Response to radiotherapy after breast-conserving surgery in different breast cancer subtypes in the Swedish Breast Cancer Group 91 radiotherapy randomized clinical trial","volume":"35","author":"Sj\u00f6str\u00f6m","year":"2017","journal-title":"J Clin Oncol Off J Am Soc Clin Oncol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3958","article-title":"The tumour microenvironment after radiotherapy: Mechanisms of resistance and recurrence","volume":"15","author":"Barker","year":"2015","journal-title":"Nat Rev Cancer"},{"key":"B20","doi-asserted-by":"publisher","first-page":"895","DOI":"10.1038\/s41401-020-0423-5","article-title":"Reversal of the immunosuppressive tumor microenvironment by nanoparticle-based activation of immune-associated cells","volume":"41","author":"Qi","year":"2020","journal-title":"Acta Pharmacol Sin"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01633","article-title":"Re-education of the tumor microenvironment with targeted therapies and immunotherapies","volume":"11","author":"Ngiow","year":"2020","journal-title":"Front Immunol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/dxy042","article-title":"Immune suppression and reversal of the suppressive tumor microenvironment","volume":"30","author":"Shimizu","year":"2018","journal-title":"Int Immunol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.Ccr-15-2711","article-title":"Maternal embryonic leucine zipper kinase (Melk) as a novel mediator and biomarker of radioresistance in human breast cancer","volume":"22","author":"Speers","year":"2016","journal-title":"Clin Cancer Res: Off J Am Assoc For Cancer Res"},{"key":"B24","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1186\/s12943-024-01990-4","article-title":"Modulation of the tumor microenvironment and mechanism of immunotherapy-based drug resistance in breast cancer","volume":"23","author":"Kundu","year":"2024","journal-title":"Mol Cancer"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2014.00001","article-title":"Radiotherapy and the tumor stroma: The importance of dose and fractionation","volume":"4","author":"Hellevik","year":"2014","journal-title":"Front Oncol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"5108","DOI":"10.1038\/s41467-018-07470-w","article-title":"Tumour-vasculature development via endothelial-to-mesenchymal transition after radiotherapy controls Cd44v6(+) cancer cell and macrophage polarization","volume":"9","author":"Choi","year":"2018","journal-title":"Nat Commun"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.7150\/jca.72893","article-title":"Construction of a novel radiosensitivity- and ferroptosis-associated gene signature for prognosis prediction in gliomas","volume":"13","author":"Xie","year":"2022","journal-title":"J Cancer"},{"key":"B28","doi-asserted-by":"publisher","first-page":"1656","DOI":"10.1016\/j.ccell.2025.06.020","article-title":"Integrated single-cell and spatial transcriptomics uncover distinct cellular subtypes involved in neural invasion in pancreatic cancer","volume":"43","author":"Chen","year":"2025","journal-title":"Cancer Cell"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202204177","article-title":"Cancer cells enter an adaptive persistence to survive radiotherapy and repopulate tumor","volume":"10","author":"Zhao","year":"2023","journal-title":"Adv Sci (Weinheim Baden-Wurttemberg Germany)"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/216709a0","article-title":"Acquired radioresistance of tumour cells","volume":"216","author":"Balmukhanov","year":"1967","journal-title":"Nature"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(21)00233-6","article-title":"Contemporary radiotherapy: Present and future","volume":"398","author":"Chandra","year":"2021","journal-title":"Lancet (London England)"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00911-1","article-title":"A single-cell and spatially resolved atlas of human breast cancers","volume":"53","author":"Wu","year":"2021","journal-title":"Nat Genet"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-019-0238-1","article-title":"A framework for advancing our understanding of cancer-associated fibroblasts","volume":"20","author":"Sahai","year":"2020","journal-title":"Nat Rev Cancer"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4419-9863-7_1384","article-title":"Irradiated mammary gland stroma promotes the expression of tumorigenic potential by unirradiated epithelial cells","volume":"60","author":"Barcellos-Hoff","year":"2000","journal-title":"Cancer Res"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-020-0246-1","article-title":"Inflammatory microenvironment remodelling by tumour cells after radiotherapy","volume":"20","author":"McLaughlin","year":"2020","journal-title":"Nat Rev Cancer"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12102916","article-title":"Tumor microenvironment as a regulator of radiation therapy: New insights into stromal-mediated radioresistance","volume":"12","author":"Krisnawan","year":"2020","journal-title":"Cancers"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3342","article-title":"The effects of deregulated DNA damage signalling on cancer chemotherapy response and resistance","volume":"12","author":"Bouwman","year":"2012","journal-title":"Nat Rev Cancer"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/nature10760","article-title":"The DNA damage response and cancer therapy","volume":"481","author":"Lord","year":"2012","journal-title":"Nature"},{"key":"B39","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1038\/s41392-020-0150-x","article-title":"DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer","volume":"5","author":"Huang","year":"2020","journal-title":"Signal Transd Targ Ther"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-med-081313-121208","article-title":"The DNA damage response: Implications for tumor responses to radiation and chemotherapy","volume":"66","author":"Goldstein","year":"2015","journal-title":"Annu Rev Med"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14225697","article-title":"Rad51 is implicated in DNA damage, chemoresistance and immune dysregulation in solid tumors","volume":"14","author":"Liao","year":"2022","journal-title":"Cancers (Basel)"},{"key":"B42","doi-asserted-by":"publisher","first-page":"4229","DOI":"10.1038\/s41598-025-88763-1","article-title":"Meta-analysis of the association between overexpression of Rad51 family genes and prognosis and clinical features in breast cancer","volume":"15","author":"Liu","year":"2025","journal-title":"Sci Rep"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1038\/nature01230","article-title":"Insights into DNA recombination from the structure of a Rad51-Brca2 complex","volume":"420","author":"Pellegrini","year":"2002","journal-title":"Nature"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.06.061","article-title":"Radx modulates Rad51 activity to control replication fork protection","volume":"24","author":"Bhat","year":"2018","journal-title":"Cell Rep"},{"key":"B45","article-title":"Elevated levels of Rad51 recombination protein in tumor cells","volume":"62","author":"Raderschall","year":"2002","journal-title":"Cancer Res"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1866358\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T05:35:09Z","timestamp":1785216909000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1866358\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,28]]},"references-count":45,"alternative-id":["10.3389\/fimmu.2026.1866358"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1866358","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,28]]},"article-number":"1866358"}}