{"title":"DNA-PKcs Dysfunction Enhances the Antitumor Activity of Radioimmunotherapy by Activating the cGAS-STING Pathway in HNSCC.","authors":"Lizhu Chen, Jing Lin, Yaoming Wen, Zeng-Qing Guo, Bin Lan, Jiani Xiong, Chuan-Ben Chen, Yu Chen","doi":"10.2147/JIR.S497295","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>Combining radiotherapy (RT) with immunotherapy for head and neck squamous cell carcinoma (HNSCC) has limited effectiveness due to the DNA damage repair (DDR) pathway activated by ionizing radiation. DNA-PK, encoded by the <i>PRKDC</i> gene, plays a key role in this repair. The potential improvement of radioimmunotherapy by inhibiting the DDR pathway is still unclear.</p><p><strong>Methods: </strong>The effectiveness of different treatments on tumor growth and survival was tested using the C3H/HeN mouse tumor model. Flow cytometry analyzed treatment-induced immunophenotypic changes. In vitro, Western blot and PCR confirmed the impact of combining immunotherapy with RT on the cGAS-STING pathway after DNA-PKcs dysfunction.</p><p><strong>Results: </strong>The combination of a DNA-PK inhibitor (NU7441), radiation therapy, and a PD-1 checkpoint inhibitor showed improved antitumor effects and extended survival in mice. Adding NU7441 into the RT and immunotherapy regimen increased CD8+ T cell infiltration. <i>PRKDC</i> alterations or DNA-PKcs dysfunction increased IR-induced DNA breaks, activating the cGAS-STING pathway and boosting the anti-tumor immune response.</p><p><strong>Conclusion: </strong>These findings suggest that targeting the DDR pathway may represent a promising therapeutic strategy and biomarker to improve the efficacy of radioimmunotherapy in HNSCC.</p>","PeriodicalId":16107,"journal":{"name":"Journal of Inflammation Research","volume":"18 ","pages":"4177-4193"},"PeriodicalIF":4.2000,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11930847/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Inflammation Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.2147/JIR.S497295","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Introduction: Combining radiotherapy (RT) with immunotherapy for head and neck squamous cell carcinoma (HNSCC) has limited effectiveness due to the DNA damage repair (DDR) pathway activated by ionizing radiation. DNA-PK, encoded by the PRKDC gene, plays a key role in this repair. The potential improvement of radioimmunotherapy by inhibiting the DDR pathway is still unclear.
Methods: The effectiveness of different treatments on tumor growth and survival was tested using the C3H/HeN mouse tumor model. Flow cytometry analyzed treatment-induced immunophenotypic changes. In vitro, Western blot and PCR confirmed the impact of combining immunotherapy with RT on the cGAS-STING pathway after DNA-PKcs dysfunction.
Results: The combination of a DNA-PK inhibitor (NU7441), radiation therapy, and a PD-1 checkpoint inhibitor showed improved antitumor effects and extended survival in mice. Adding NU7441 into the RT and immunotherapy regimen increased CD8+ T cell infiltration. PRKDC alterations or DNA-PKcs dysfunction increased IR-induced DNA breaks, activating the cGAS-STING pathway and boosting the anti-tumor immune response.
Conclusion: These findings suggest that targeting the DDR pathway may represent a promising therapeutic strategy and biomarker to improve the efficacy of radioimmunotherapy in HNSCC.
期刊介绍:
An international, peer-reviewed, open access, online journal that welcomes laboratory and clinical findings on the molecular basis, cell biology and pharmacology of inflammation.