Increased activation of cGAS-STING pathway enhances radiosensitivity of non-small cell lung cancer cells

Background: Radiotherapy is an effective therapeutic approach widely used clinically in non-small cell lung cancer (NSCLC), but radioresistance remains a major challenge. New and effective radiosensitizing approaches are thus urgently needed. The activation of DNA-sensing cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has become an attractive therapeutic target, but the relationship between activation of cGAS-STING pathway and radiosensitization of NSCLC cells remains unknown.

Methods: Considering low expression of cGAS-STING pathway genes in NSCLC, including STING, we used an activator (STING agonist, dimeric amidobenzimidazole [diABZI]) of cGAS-STING pathway and increased activation factor (DNA double strand breaks) of cGAS-STING pathway to respectively reinforce the activation of cGAS-STING pathway in NSCLC cells. We then investigated the effect of increased activation of cGAS-STING pathway on the proliferation of H460 and A549 cells by CCK-8 and colony formation assays, and revealed the underlying mechanism.

Results: We found that both diABZI and the increased DNA double strand breaks could sensitize NSCLC cells to irradiation. Mechanically, our results showed that the increased activation of cGAS-STING pathway enhanced radiosensitivity by promoting apoptosis in NSCLC cells.

Conclusion: Taken together, we concluded that diABZI could be used as a radiosensitizer in NSCLC cells, and targeting the activation of cGAS-STING pathway has a potential to be a new approach for NSCLC radiosensitizing.