Immunotherapy enhances the risk of tumor oxidative stress and metastasis in lung cancer with radiation pneumonitis
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 im...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2025-07-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1629170/full |
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| author | Ruidi Jiao Ruidi Jiao Wenbo Xu Kunpeng Xu Mingxia Zhang Weilong Liu Wei Jiang Wei Jiang Luhua Wang Luhua Wang |
| author_facet | Ruidi Jiao Ruidi Jiao Wenbo Xu Kunpeng Xu Mingxia Zhang Weilong Liu Wei Jiang Wei Jiang Luhua Wang Luhua Wang |
| author_sort | Ruidi Jiao |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-976f16d4972f428ebadd23067b7d2d7d |
| institution | DOAJ |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-976f16d4972f428ebadd23067b7d2d7d2025-08-20T03:15:20ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-07-011610.3389/fimmu.2025.16291701629170Immunotherapy enhances the risk of tumor oxidative stress and metastasis in lung cancer with radiation pneumonitisRuidi Jiao0Ruidi Jiao1Wenbo Xu2Kunpeng Xu3Mingxia Zhang4Weilong Liu5Wei Jiang6Wei Jiang7Luhua Wang8Luhua Wang9School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, ChinaDepartment of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, Guangdong, ChinaThe Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, Gansu, ChinaDepartment of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, Guangdong, ChinaShenzhen Key Laboratory of Infection and Immunity, Shenzhen Third People’s Hospital, Shenzhen, Guangdong, ChinaShenzhen Key Laboratory of Infection and Immunity, Shenzhen Third People’s Hospital, Shenzhen, Guangdong, ChinaSchool of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, ChinaDepartment of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, Guangdong, ChinaSchool of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, ChinaDepartment of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, Guangdong, ChinaRadiation 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.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1629170/fullradiation pneumonitisimmunotherapymetastasisoxidative stresslung cancer |
| spellingShingle | Ruidi Jiao Ruidi Jiao Wenbo Xu Kunpeng Xu Mingxia Zhang Weilong Liu Wei Jiang Wei Jiang Luhua Wang Luhua Wang Immunotherapy enhances the risk of tumor oxidative stress and metastasis in lung cancer with radiation pneumonitis Frontiers in Immunology radiation pneumonitis immunotherapy metastasis oxidative stress lung cancer |
| title | Immunotherapy enhances the risk of tumor oxidative stress and metastasis in lung cancer with radiation pneumonitis |
| title_full | Immunotherapy enhances the risk of tumor oxidative stress and metastasis in lung cancer with radiation pneumonitis |
| title_fullStr | Immunotherapy enhances the risk of tumor oxidative stress and metastasis in lung cancer with radiation pneumonitis |
| title_full_unstemmed | Immunotherapy enhances the risk of tumor oxidative stress and metastasis in lung cancer with radiation pneumonitis |
| title_short | Immunotherapy enhances the risk of tumor oxidative stress and metastasis in lung cancer with radiation pneumonitis |
| title_sort | immunotherapy enhances the risk of tumor oxidative stress and metastasis in lung cancer with radiation pneumonitis |
| topic | radiation pneumonitis immunotherapy metastasis oxidative stress lung cancer |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1629170/full |
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