Exosome PAICS promotes radioresistance of non-small cell lung cancer through reducing radition-induced DNA damage and promoting immune escape via STING signaling pathway

Background The development of radiotherapy resistance is a process involving complicated mechanisms, in which tumor-derived exosomes play an important role. Methods Colony formation assay, wound healing assay and immunofluorescence assay were adopted to examine the the effects of radioresistant cell-derived exosomes on the radiosensitivity of receptor NSCLC cells. RNA sequencing was performed to identify the functional gene of radioresistant NSCLC cells. A series of in vitro and in vivo experiments, such as the subcutaneous transplantation tumor model and the flow cytometry, were adopted to study the effect of the functional protein transported by exosomes on NSCLC and the mechanisms invloved. Results We found that radioresistant A549 cell-derived exosomes could attenuate the lethal DNA damage and enhance the radio-resistance of co-cultured NSCLC cells. Phosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS) was significantly up-regulated in A549/X and A549/X-derived exosomes, suggesting that exosome PAICS may be involved in the development of radio-resistance in NSCLC. The killing effects of irradiation in NSCLC cells were partially restored when reducing PAICS of exosome. The STING signalling pathway was influenced by PAICS. Moreover, The irradiation-mediated tumor regression was weakened when giving A549/X cell-derived exosomes intravenously before radiotherapy. The animal experiments also indicated that exosome PAICS could restrain the tumor regression effect of irradiation through inducing immunosuppressive macroenvironment and promote tumor immune escape. Conclusion Our findings indicate that PAICS, a key enzyme in the purine de novo synthesis pathway, could be transported to the receptor NSCLC cells through exosomes, which might be an important way to cause NSCLC radiotherapy resistance.