DNA-PKcs Dysfunction Enhances the Antitumor Activity of Radioimmunotherapy by Activating the cGAS-STING Pathway in HNSCC.

IF 4.2 2区 医学 Q2 IMMUNOLOGY
Journal of Inflammation Research Pub Date : 2025-03-19 eCollection Date: 2025-01-01 DOI:10.2147/JIR.S497295
Lizhu Chen, Jing Lin, Yaoming Wen, Zeng-Qing Guo, Bin Lan, Jiani Xiong, Chuan-Ben Chen, Yu Chen
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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.

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来源期刊
Journal of Inflammation Research
Journal of Inflammation Research Immunology and Microbiology-Immunology
CiteScore
6.10
自引率
2.20%
发文量
658
审稿时长
16 weeks
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.
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