{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T06:27:58Z","timestamp":1786343278249,"version":"build-2736575974"},"reference-count":74,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"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:p>\n                    Radiotherapy (RT) is a widely used treatment modality for breast cancer, but its broad application is limited by the risk of adverse effects, such as the potential for the tumor to develop resistance to RT. Identifying strategies that enhance RT efficacy while minimizing adverse effects is of significant clinical importance. Valproic acid (VPA), an anti-epileptic drug, has shown promise in augmenting the efficacy of RT, though its underlying mechanisms remain unclear. We established\n                    <jats:italic>in vitro<\/jats:italic>\n                    co-culture systems and in vivo breast tumor models, and performed multiple molecular and cellular assays to investigate the immunological mechanism underlying VPA-mediated tumor radiosensitization. In this study, we demonstrated that VPA enhances the radiosensitivity of breast tumor by activating the \u03b2TrCP-NF-\u03baB immune pathway, which reprograms tumor-associated macrophages (TAMs) into the M1 phenotype. VPA suppresses HDAC1\/2 activity, which in turn upregulates \u03b2TrCP expression, accelerating ubiquitination and degradation of the NF-\u03baB suppressor I\u03baB\u03b1. In normal tissues, VPA suppresses the inflammatory response triggered by the \u03b2TrCP-NF-\u03baB pathway. This bidirectional regulatory effect of VPA reveals a novel immunological mechanism for its application as a RT adjuvant, offering both enhanced tumor radiosensitivity and radioprotection of normal tissues.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1839063","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T05:30:47Z","timestamp":1786339847000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Macrophage polarization regulated by the \u03b2TrCP-NF-\u03baB inflammatory signaling pathway is required for valproic acid\u2019s dual role in breast tumor radiosensitivity and normal tissue radioprotection"],"prefix":"10.3389","volume":"17","author":[{"given":"Beidi","family":"Jia","sequence":"first","affiliation":[{"name":"Department of Occupational and Environmental Health, School of Public Health, Cheeloo College of Medicine, Shandong University","place":["Shandong, Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guochao","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Occupational and Environmental Health, School of Public Health, Cheeloo College of Medicine, Shandong University","place":["Shandong, Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Lim","sequence":"additional","affiliation":[{"name":"Faculty of Health, University of Technology Sydney","place":["Ultimo, NSW, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quanji","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Occupational and Environmental Health, School of Public Health, Cheeloo College of Medicine, Shandong University","place":["Shandong, Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songying","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Occupational and Environmental Health, School of Public Health, Cheeloo College of Medicine, Shandong University","place":["Shandong, Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihui","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Occupational and Environmental Health, School of Public Health, Cheeloo College of Medicine, Shandong University","place":["Shandong, Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,10]]},"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":"10.1038\/nrc2587","article-title":"Normal tissue reactions to radiotherapy: towards tailoring treatment dose by genotype","volume":"9","author":"Barnett","year":"2009","journal-title":"Nat Rev Cancer"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.21873\/anticanres.16212","article-title":"Breast conserving surgery in combination with targeted intraoperative radiotherapy compared to mastectomy for in-breast-tumor-recurrence","volume":"43","author":"Kolberg","year":"2023","journal-title":"Anticancer Res"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2025.103712","article-title":"Supplementing sialic acid analogs overcomes radiotherapy resistance in triple-negative breast cancer by exacerbating ER stress","volume":"85","author":"Yang","year":"2025","journal-title":"Redox Biol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-021-00568-1","article-title":"Immunomodulation by radiotherapy in tumour control and normal tissue toxicity","volume":"22","author":"Cytlak","year":"2022","journal-title":"Nat Rev Immunol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2020.12.015","article-title":"Epigenetics of glioblastoma multiforme: From molecular mechanisms to therapeutic approaches","volume":"83","author":"Uddin","year":"2022","journal-title":"Semin Cancer Biol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1038\/icb.2011.92","article-title":"HDACi: molecular mechanisms and therapeutic implications in the innate immune system","volume":"90","author":"Suliman","year":"2012","journal-title":"Immunol Cell Biol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1586\/14737140.2014.940329","article-title":"Could valproic acid be an effective anticancer agent? 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