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.

Background To identify radio‐responsive genes and explore the biological function of encoded proteins in non‐small cell lung cancer (NSCLC). Methods Radio‐responsive genes in irradiated H460 cells were screened from microarray data deposited in the Gene Expression Omnibus (GEO) database. A quantitative real time polymerase chain reaction assay was used to detect the expression of candidate radio‐responsive genes in irradiated cells. CCK‐8 assay, EDU assay, clone formation assay, immunofluorescence and flow cytometry were conducted to evaluate the biological function of B cell translocation gene 2 (BTG2) in NSCLC. Results Bioinformatic analysis using GES20549 showed that BTG2 was a radio‐responsive gene in irradiated H460 cells. The mRNA expression level of BTG2 was lower in H460 cells compared with that in BEAS‐2B normal lung epithelial cells. BTG2 expression was elevated upon IR exposure, in a dose‐dependent but not a time‐dependent manner. CCK‐8 and EDU assays revealed that BTG2 overexpression inhibited the growth rate of irradiated cells. Clone formation showed that elevated BTG2 promoted DNA damage of irradiated H460 cells. The number of γ‐H2AX foci induced by DNA damage was also markedly increased upon BTG2 overexpression. Flow cytometry showed that BTG2 increased IR‐induced cell apoptosis. Conclusions BTG2 may be a novel radio‐responsive factor and a promising therapeutic target for radiotherapy of NSCLC.