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 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.