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

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 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. 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.