{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T15:24:13Z","timestamp":1787066653991,"version":"build-2736575974"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,24]],"date-time":"2025-07-24T00:00:00Z","timestamp":1753315200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Radiation pneumonitis (RP) is a prevalent complication associated with lung cancer radiotherapy; nonetheless, its effects on lung cancer immunotherapy and the underlying biological mechanisms remain inadequately elucidated. Utilizing mouse models of RP and orthotopically lung cancer, we witnessed immunotherapy-enhanced liver metastasis of lung cancer within the context of RP, accompanied by increased neutrophil infiltration of the primary tumor. Analysis of metabolic adaptations driven by the inflammatory microenvironment during treatment revealed that RP and immunotherapy act synergistically to exacerbate lipid metabolic dysregulation and oxidative stress. Integrating clinical validation with single-cell RNA sequencing data from a multicenter lung adenocarcinoma cohort, we demonstrated that elevated oxidative stress scores within tumor tissue were significantly associated with both diminished response to immunotherapy and unfavorable clinical outcomes. These findings coincided with alterations in the tumor immune microenvironment, notably a marked increase in neutrophils and activated mast cells. This investigation highlights that RP is not merely a toxicity but an active modulator of the tumor-immune-metabolism landscape. By dissecting the RP-ICB-metabolism axis, we have elucidated a novel mechanism underlying immunotherapy resistance, offering new insights into the rational design of optimized radioimmunotherapy.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1629170","type":"journal-article","created":{"date-parts":[[2025,7,24]],"date-time":"2025-07-24T05:33:01Z","timestamp":1753335181000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Immunotherapy enhances the risk of tumor oxidative stress and metastasis in lung cancer with radiation pneumonitis"],"prefix":"10.3389","volume":"16","author":[{"given":"Ruidi","family":"Jiao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenbo","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kunpeng","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingxia","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weilong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luhua","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,7,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-023-00798-3","article-title":"The global burden of lung cancer: current status and future trends","volume":"20","author":"Leiter","year":"2023","journal-title":"Nat Rev Clin Oncol"},{"key":"B2","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 Cancer J Clin"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.21.01308","article-title":"Five-year survival outcomes from the pacific trial: durvalumab after chemoradiotherapy in stage iii non-small-cell lung cancer","volume":"40","author":"Spigel","year":"2022","journal-title":"J Clin Oncol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.823618","article-title":"Immunotherapy in lung cancer: current landscape and future directions","volume":"13","author":"Mamdani","year":"2022","journal-title":"Front Immunol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1111\/ajco.13688","article-title":"Safety and potential increased risk of toxicity of radiotherapy combined immunotherapy strategy","volume":"19","author":"Guan","year":"2023","journal-title":"Asia Pac J Clin Oncol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.2217\/fon-2022-1274","article-title":"Pneumonitis with combined immune checkpoint inhibitors and chemoradiotherapy in locally advanced non-small-cell lung cancer: A systematic review and meta-analysis","volume":"19","author":"Yang","year":"2023","journal-title":"Future Oncol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.918787","article-title":"Comprehensive pneumonitis profile of thoracic radiotherapy followed by immune checkpoint inhibitor and risk factors for radiation recall pneumonitis in lung cancer","volume":"13","author":"Lu","year":"2022","journal-title":"Front Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.21037\/tlcr-20-838","article-title":"Pd-1 restrains il-17a production from gammadelta T cells to modulate acute radiation-induced lung injury","volume":"10","author":"Sheng","year":"2021","journal-title":"Transl Lung Cancer Res"},{"key":"B9","doi-asserted-by":"publisher","first-page":"e25665","DOI":"10.7759\/cureus.25665","article-title":"Comparison of pneumonitis rates and severity in patients with lung cancer treated by immunotherapy, radiotherapy, and immunoradiotherapy","volume":"14","author":"Aiad","year":"2022","journal-title":"Cureus"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2023.09.050","article-title":"Pneumonitis after chemoradiotherapy and adjuvant durvalumab in stage iii non-small cell lung cancer","volume":"118","author":"Edwards","year":"2024","journal-title":"Int J Radiat Oncol Biol Phys"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1080\/08923973.2018.1533025","article-title":"Radiation-induced lung injury: impact on macrophage dysregulation and lipid alteration - a review","volume":"41","author":"NS","year":"2019","journal-title":"Immunopharmacol Immunotoxicol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1020","DOI":"10.3390\/metabo13091020","article-title":"Metabolomic signatures associated with radiation-induced lung injury by correlating lung tissue to plasma in a rat model","volume":"13","author":"Gu","year":"2023","journal-title":"Metabolites"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1039\/d4an00152d","article-title":"Metabolic profiling of murine radiation-induced lung injury with raman spectroscopy and comparative machine learning","volume":"149","author":"Wiebe","year":"2024","journal-title":"Analyst"},{"key":"B14","doi-asserted-by":"publisher","first-page":"e008811","DOI":"10.1136\/jitc-2024-008811","article-title":"Harnessing lipid metabolism modulation for improved immunotherapy outcomes in lung adenocarcinoma","volume":"12","author":"Chen","year":"2024","journal-title":"J Immunother Cancer"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.18632\/aging.205838","article-title":"Prediction of prognosis and immunotherapy efficacy based on metabolic landscape in lung adenocarcinoma by bulk, single-cell rna sequencing and mendelian randomization analyses","volume":"16","author":"Liu","year":"2024","journal-title":"Aging (Albany NY)"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1007\/BF00300234","article-title":"Determination of subcutaneous tumor size in athymic (Nude) mice","volume":"24","author":"Tomayko","year":"1989","journal-title":"Cancer Chemother Pharmacol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2009.06.017","article-title":"Polarization of tumor-associated neutrophil phenotype by tgf-beta: \u201cN1\u201d Versus \u201cN2\u201d Tan","volume":"16","author":"Fridlender","year":"2009","journal-title":"Cancer Cell"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0134-3","article-title":"Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab","volume":"24","author":"Gandara","year":"2018","journal-title":"Nat Med"},{"key":"B19","doi-asserted-by":"publisher","first-page":"e20201606","DOI":"10.1084\/jem.20201606","article-title":"Lipid metabolism and cancer","volume":"218","author":"Bian","year":"2021","journal-title":"J Exp Med"},{"key":"B20","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1038\/s43018-023-00702-z","article-title":"Lipids as mediators of cancer progression and metastasis","volume":"5","author":"Vogel","year":"2024","journal-title":"Nat Cancer"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2022.09.023","article-title":"The role of lipids in cancer progression and metastasis","volume":"34","author":"Martin-Perez","year":"2022","journal-title":"Cell Metab"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1322746","article-title":"Lipid peroxidation of immune cells in cancer","volume":"14","author":"Xiao","year":"2023","journal-title":"Front Immunol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1016\/j.cell.2024.10.047","article-title":"Acsl4 and polyunsaturated lipids support metastatic extravasation and colonization","volume":"188","author":"Wang","year":"2025","journal-title":"Cell"},{"key":"B24","doi-asserted-by":"publisher","first-page":"e2400676","DOI":"10.1002\/advs.202400676","article-title":"Hepatocellular carcinoma linc01116 outcompetes T cells for linoleic acid and accelerates tumor progression","volume":"11","author":"Ma","year":"2024","journal-title":"Adv Sci (Weinh)"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1007\/s10555-020-09904-8","article-title":"Role of linoleic acid-derived oxylipins in cancer","volume":"39","author":"Edin","year":"2020","journal-title":"Cancer Metastasis Rev"},{"key":"B26","doi-asserted-by":"publisher","first-page":"1185","DOI":"10.1016\/j.immuni.2022.06.001","article-title":"Very-low-density lipoprotein receptor-enhanced lipid metabolism in pancreatic stellate cells promotes pancreatic fibrosis","volume":"55","author":"Yang","year":"2022","journal-title":"Immunity"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2024.103096","article-title":"Excessive linoleic acid induces muscle oxidative stress through 5-lipoxygenase-dependent peroxidation","volume":"71","author":"Cao","year":"2024","journal-title":"Redox Biol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"e1180","DOI":"10.1002\/ctm2.1180","article-title":"Lysophosphatidylcholine inhibits lung cancer cell proliferation by regulating fatty acid metabolism enzyme long-chain acyl-coenzyme a synthase 5","volume":"13","author":"Zhang","year":"2023","journal-title":"Clin Transl Med"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1782","DOI":"10.3390\/ijms24021782","article-title":"The road to Malignant cell transformation after particulate matter exposure: from oxidative stress to genotoxicity","volume":"24","author":"Santibanez-Andrade","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1007\/s12010-022-04266-z","article-title":"Regulatory components of oxidative stress and inflammation and their complex interplay in carcinogenesis","volume":"195","author":"Dharshini","year":"2023","journal-title":"Appl Biochem Biotechnol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"6062","DOI":"10.3390\/cancers13236062","article-title":"Therapeutic influence on important targets associated with chronic inflammation and oxidative stress in cancer treatment","volume":"13","author":"Neganova","year":"2021","journal-title":"Cancers (Basel)"},{"key":"B32","doi-asserted-by":"publisher","first-page":"e2306929","DOI":"10.1002\/advs.202306929","article-title":"Oxidative stress promotes liver cancer metastasis via rnf25-mediated E-cadherin protein degradation","volume":"11","author":"Huang","year":"2024","journal-title":"Adv Sci (Weinh)"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/nature07733","article-title":"Association of reactive oxygen species levels and radioresistance in cancer stem cells","volume":"458","author":"Diehn","year":"2009","journal-title":"Nature"},{"key":"B34","doi-asserted-by":"publisher","first-page":"3292","DOI":"10.1038\/s41598-021-82976-w","article-title":"Integrated analysis identifies oxidative stress genes associated with progression and prognosis in gastric cancer","volume":"11","author":"Wu","year":"2021","journal-title":"Sci Rep"},{"key":"B35","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1186\/s12859-023-05203-5","article-title":"Integrated analysis identifies oxidative stress-related lncrnas associated with progression and prognosis in colorectal cancer","volume":"24","author":"Chen","year":"2023","journal-title":"BMC Bioinf"},{"key":"B36","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1186\/s12967-023-03970-6","article-title":"Identification and validation of a novel prognostic signature based on mitochondria and oxidative stress related genes for glioblastoma","volume":"21","author":"Tong","year":"2023","journal-title":"J Transl Med"},{"key":"B37","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1038\/s41573-024-00979-4","article-title":"Targeting ros in cancer: rationale and strategies","volume":"23","author":"Glorieux","year":"2024","journal-title":"Nat Rev Drug Discov"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2022.215783","article-title":"Fangchinoline inhibits non-small cell lung cancer metastasis by reversing epithelial-mesenchymal transition and suppressing the cytosolic ros-related akt-mtor signaling pathway","volume":"543","author":"Chen","year":"2022","journal-title":"Cancer Lett"},{"key":"B39","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1186\/s13578-022-00944-x","article-title":"Discovery and mechanism studies of a novel atg4b inhibitor ebselen by drug repurposing and its anti-colorectal cancer effects in mice","volume":"12","author":"Xie","year":"2022","journal-title":"Cell Biosci"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2022.114134","article-title":"Brusatol: A potential sensitizing agent for cancer therapy from brucea javanica","volume":"158","author":"He","year":"2023","journal-title":"BioMed Pharmacother"},{"key":"B41","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1186\/s40001-023-01290-5","article-title":"Identification of molecular subgroups and establishment of risk model based on the response to oxidative stress to predict overall survival of patients with lung adenocarcinoma","volume":"28","author":"Liu","year":"2023","journal-title":"Eur J Med Res"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2023.1078697","article-title":"A novel prognostic model related to oxidative stress for treatment prediction in lung adenocarcinoma","volume":"13","author":"Peng","year":"2023","journal-title":"Front Oncol"},{"key":"B43","doi-asserted-by":"publisher","first-page":"e2406748121","DOI":"10.1073\/pnas.2406748121","article-title":"Platelet-activating factor (Paf) promotes immunosuppressive neutrophil differentiation within tumors","volume":"121","author":"Dahal","year":"2024","journal-title":"Proc Natl Acad Sci U.S.A"},{"key":"B44","doi-asserted-by":"publisher","first-page":"e130850","DOI":"10.1172\/jci.insight.130850","article-title":"Neutrophil content predicts lymphocyte depletion and anti-pd1 treatment failure in nsclc","volume":"4","author":"Kargl","year":"2019","journal-title":"JCI Insight"},{"key":"B45","doi-asserted-by":"publisher","first-page":"1359","DOI":"10.3390\/cancers14051359","article-title":"Neutrophil extracellular traps in cancer therapy resistance","volume":"14","author":"Shahzad","year":"2022","journal-title":"Cancers (Basel)"},{"key":"B46","doi-asserted-by":"publisher","first-page":"e20190354","DOI":"10.1084\/jem.20190354","article-title":"Interleukin-17-induced neutrophil extracellular traps mediate resistance to checkpoint blockade in pancreatic cancer","volume":"217","author":"Zhang","year":"2020","journal-title":"J Exp Med"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-0915-y","article-title":"Neutrophils escort circulating tumour cells to enable cell cycle progression","volume":"566","author":"Szczerba","year":"2019","journal-title":"Nature"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2021-326070","article-title":"Single-cell rna-seq analysis reveals bhlhe40-driven pro-tumour neutrophils with hyperactivated glycolysis in pancreatic tumour microenvironment","volume":"72","author":"Wang","year":"2023","journal-title":"Gut"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1629170\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,24]],"date-time":"2025-07-24T05:33:03Z","timestamp":1753335183000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1629170\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,24]]},"references-count":48,"alternative-id":["10.3389\/fimmu.2025.1629170"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1629170","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,24]]},"article-number":"1629170"}}