Ultra-high dose rate radiotherapy overcomes radioresistance in head and neck squamous cell carcinoma
Abstract Radiotherapy (RT) resistance in head and neck squamous cell carcinoma (HNSCC) significantly hampers local control and patient prognosis. This study investigated the efficacy and molecular mechanisms of high-energy X-ray-based ultra-high dose rate radiotherapy (UHDR-RT) in overcoming RT resi...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2025-03-01
|
| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-025-02184-0 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850028076704989184 |
|---|---|
| author | Hong-Shuai Li Ruo Tang Hua-Shan Shi Zi-Jian Qin Xiao-Yang Zhang Yun-Fei Sun Zhi-Gong Wei Chao-Fan Ma Liu Yang Ye Chen Zhe-Ran Liu Li-Li Zhu Wen Yang Li Yang Ai-Ning Xu Zhuo Zhang Shu-Qing Liao Jin-Shui Shi Jian-Jun Deng Xiao-Zhong He Xing-Chen Peng |
| author_facet | Hong-Shuai Li Ruo Tang Hua-Shan Shi Zi-Jian Qin Xiao-Yang Zhang Yun-Fei Sun Zhi-Gong Wei Chao-Fan Ma Liu Yang Ye Chen Zhe-Ran Liu Li-Li Zhu Wen Yang Li Yang Ai-Ning Xu Zhuo Zhang Shu-Qing Liao Jin-Shui Shi Jian-Jun Deng Xiao-Zhong He Xing-Chen Peng |
| author_sort | Hong-Shuai Li |
| collection | DOAJ |
| description | Abstract Radiotherapy (RT) resistance in head and neck squamous cell carcinoma (HNSCC) significantly hampers local control and patient prognosis. This study investigated the efficacy and molecular mechanisms of high-energy X-ray-based ultra-high dose rate radiotherapy (UHDR-RT) in overcoming RT resistance. The established RT-resistant HNSCC cell lines and animal models were subjected to UHDR-RT or conventional RT (Conv-RT) via a high-power rhodotron accelerator. Cellular assays assessed the malignant phenotype, viability, and degree of DNA damage, whereas in vivo evaluations focused on tumor proliferation and the tumor immune microenvironment (TiME). Transcriptome sequencing and Olink proteomics were employed to explore the underlying mechanisms involved. In vitro experiments indicated that UHDR-RT suppressed radioresistant cell proliferation and invasion, while promoting apoptosis and exacerbating DNA damage. In contrast, its efficacy in radiosensitive cells was comparable to that of Conv-RT. In vivo studies using patient-derived xenograft nude mice models demonstrated that UHDR-RT only partially reversed RT resistance. Transcriptomic and proteomic analyses of C57BL/6J mice models revealed the predominant role of TiME modulating in reversing radioresistance. Immunofluorescence and flow cytometry confirmed increased CD8+ T cells and an increased M1/M2 macrophage ratio post-UHDR-RT. Mechanistically, UHDR-RT activated CD8+ T cells, which stimulated M1 macrophages through paracrine IFN-γ signaling, thereby enhancing TiME activation. Furthermore, the activated M1 macrophages secreted CXCL9, which in turn reactivated CD8+ T cells, forming a feedforward loop that amplified TiME activation. This study elucidates the dual role of UHDR-RT in directly inducing DNA damage and modulating the TiME, highlighting its potential in treating radioresistant HNSCC. |
| format | Article |
| id | doaj-art-4187e4cf8f564d83b2f97bfdb53ea232 |
| institution | DOAJ |
| issn | 2059-3635 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Signal Transduction and Targeted Therapy |
| spelling | doaj-art-4187e4cf8f564d83b2f97bfdb53ea2322025-08-20T02:59:57ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352025-03-0110111710.1038/s41392-025-02184-0Ultra-high dose rate radiotherapy overcomes radioresistance in head and neck squamous cell carcinomaHong-Shuai Li0Ruo Tang1Hua-Shan Shi2Zi-Jian Qin3Xiao-Yang Zhang4Yun-Fei Sun5Zhi-Gong Wei6Chao-Fan Ma7Liu Yang8Ye Chen9Zhe-Ran Liu10Li-Li Zhu11Wen Yang12Li Yang13Ai-Ning Xu14Zhuo Zhang15Shu-Qing Liao16Jin-Shui Shi17Jian-Jun Deng18Xiao-Zhong He19Xing-Chen Peng20Department of Biotherapy, Cancer Center, and National Clinical Research Center for Geriatrics, West China Hospital of Sichuan UniversityInstitute of Fluid Physics, Chinese Academy of Engineering PhysicsDepartment of Biotherapy, Cancer Center, and National Clinical Research Center for Geriatrics, West China Hospital of Sichuan UniversityDepartment of Biotherapy, Cancer Center, and National Clinical Research Center for Geriatrics, West China Hospital of Sichuan UniversityInstitute of Fluid Physics, Chinese Academy of Engineering PhysicsInstitute of Fluid Physics, Chinese Academy of Engineering PhysicsDepartment of Biotherapy, Cancer Center, and National Clinical Research Center for Geriatrics, West China Hospital of Sichuan UniversityInstitute of Fluid Physics, Chinese Academy of Engineering PhysicsInstitute of Fluid Physics, Chinese Academy of Engineering PhysicsDepartment of Biotherapy, Cancer Center, and National Clinical Research Center for Geriatrics, West China Hospital of Sichuan UniversityDepartment of Biotherapy, Cancer Center, and National Clinical Research Center for Geriatrics, West China Hospital of Sichuan UniversityDepartment of Biotherapy, Cancer Center, and National Clinical Research Center for Geriatrics, West China Hospital of Sichuan UniversityInstitute of Fluid Physics, Chinese Academy of Engineering PhysicsDepartment of Biotherapy, Cancer Center, and National Clinical Research Center for Geriatrics, West China Hospital of Sichuan UniversityDepartment of Applied Statistics, Social Science, and Humanities, New York UniversityInstitute of Fluid Physics, Chinese Academy of Engineering PhysicsInstitute of Fluid Physics, Chinese Academy of Engineering PhysicsInstitute of Fluid Physics, Chinese Academy of Engineering PhysicsInstitute of Fluid Physics, Chinese Academy of Engineering PhysicsInstitute of Fluid Physics, Chinese Academy of Engineering PhysicsDepartment of Biotherapy, Cancer Center, and National Clinical Research Center for Geriatrics, West China Hospital of Sichuan UniversityAbstract Radiotherapy (RT) resistance in head and neck squamous cell carcinoma (HNSCC) significantly hampers local control and patient prognosis. This study investigated the efficacy and molecular mechanisms of high-energy X-ray-based ultra-high dose rate radiotherapy (UHDR-RT) in overcoming RT resistance. The established RT-resistant HNSCC cell lines and animal models were subjected to UHDR-RT or conventional RT (Conv-RT) via a high-power rhodotron accelerator. Cellular assays assessed the malignant phenotype, viability, and degree of DNA damage, whereas in vivo evaluations focused on tumor proliferation and the tumor immune microenvironment (TiME). Transcriptome sequencing and Olink proteomics were employed to explore the underlying mechanisms involved. In vitro experiments indicated that UHDR-RT suppressed radioresistant cell proliferation and invasion, while promoting apoptosis and exacerbating DNA damage. In contrast, its efficacy in radiosensitive cells was comparable to that of Conv-RT. In vivo studies using patient-derived xenograft nude mice models demonstrated that UHDR-RT only partially reversed RT resistance. Transcriptomic and proteomic analyses of C57BL/6J mice models revealed the predominant role of TiME modulating in reversing radioresistance. Immunofluorescence and flow cytometry confirmed increased CD8+ T cells and an increased M1/M2 macrophage ratio post-UHDR-RT. Mechanistically, UHDR-RT activated CD8+ T cells, which stimulated M1 macrophages through paracrine IFN-γ signaling, thereby enhancing TiME activation. Furthermore, the activated M1 macrophages secreted CXCL9, which in turn reactivated CD8+ T cells, forming a feedforward loop that amplified TiME activation. This study elucidates the dual role of UHDR-RT in directly inducing DNA damage and modulating the TiME, highlighting its potential in treating radioresistant HNSCC.https://doi.org/10.1038/s41392-025-02184-0 |
| spellingShingle | Hong-Shuai Li Ruo Tang Hua-Shan Shi Zi-Jian Qin Xiao-Yang Zhang Yun-Fei Sun Zhi-Gong Wei Chao-Fan Ma Liu Yang Ye Chen Zhe-Ran Liu Li-Li Zhu Wen Yang Li Yang Ai-Ning Xu Zhuo Zhang Shu-Qing Liao Jin-Shui Shi Jian-Jun Deng Xiao-Zhong He Xing-Chen Peng Ultra-high dose rate radiotherapy overcomes radioresistance in head and neck squamous cell carcinoma Signal Transduction and Targeted Therapy |
| title | Ultra-high dose rate radiotherapy overcomes radioresistance in head and neck squamous cell carcinoma |
| title_full | Ultra-high dose rate radiotherapy overcomes radioresistance in head and neck squamous cell carcinoma |
| title_fullStr | Ultra-high dose rate radiotherapy overcomes radioresistance in head and neck squamous cell carcinoma |
| title_full_unstemmed | Ultra-high dose rate radiotherapy overcomes radioresistance in head and neck squamous cell carcinoma |
| title_short | Ultra-high dose rate radiotherapy overcomes radioresistance in head and neck squamous cell carcinoma |
| title_sort | ultra high dose rate radiotherapy overcomes radioresistance in head and neck squamous cell carcinoma |
| url | https://doi.org/10.1038/s41392-025-02184-0 |
| work_keys_str_mv | AT hongshuaili ultrahighdoserateradiotherapyovercomesradioresistanceinheadandnecksquamouscellcarcinoma AT ruotang ultrahighdoserateradiotherapyovercomesradioresistanceinheadandnecksquamouscellcarcinoma AT huashanshi ultrahighdoserateradiotherapyovercomesradioresistanceinheadandnecksquamouscellcarcinoma AT zijianqin ultrahighdoserateradiotherapyovercomesradioresistanceinheadandnecksquamouscellcarcinoma AT xiaoyangzhang ultrahighdoserateradiotherapyovercomesradioresistanceinheadandnecksquamouscellcarcinoma AT yunfeisun ultrahighdoserateradiotherapyovercomesradioresistanceinheadandnecksquamouscellcarcinoma AT zhigongwei ultrahighdoserateradiotherapyovercomesradioresistanceinheadandnecksquamouscellcarcinoma AT chaofanma ultrahighdoserateradiotherapyovercomesradioresistanceinheadandnecksquamouscellcarcinoma AT liuyang ultrahighdoserateradiotherapyovercomesradioresistanceinheadandnecksquamouscellcarcinoma AT yechen ultrahighdoserateradiotherapyovercomesradioresistanceinheadandnecksquamouscellcarcinoma AT zheranliu ultrahighdoserateradiotherapyovercomesradioresistanceinheadandnecksquamouscellcarcinoma AT lilizhu ultrahighdoserateradiotherapyovercomesradioresistanceinheadandnecksquamouscellcarcinoma AT wenyang ultrahighdoserateradiotherapyovercomesradioresistanceinheadandnecksquamouscellcarcinoma AT liyang ultrahighdoserateradiotherapyovercomesradioresistanceinheadandnecksquamouscellcarcinoma AT ainingxu ultrahighdoserateradiotherapyovercomesradioresistanceinheadandnecksquamouscellcarcinoma AT zhuozhang ultrahighdoserateradiotherapyovercomesradioresistanceinheadandnecksquamouscellcarcinoma AT shuqingliao ultrahighdoserateradiotherapyovercomesradioresistanceinheadandnecksquamouscellcarcinoma AT jinshuishi ultrahighdoserateradiotherapyovercomesradioresistanceinheadandnecksquamouscellcarcinoma AT jianjundeng ultrahighdoserateradiotherapyovercomesradioresistanceinheadandnecksquamouscellcarcinoma AT xiaozhonghe ultrahighdoserateradiotherapyovercomesradioresistanceinheadandnecksquamouscellcarcinoma AT xingchenpeng ultrahighdoserateradiotherapyovercomesradioresistanceinheadandnecksquamouscellcarcinoma |