放疗联合EGFR-TKI显著改善EGFRm NSCLC脑转移患者预后，然而仍会复发。文献报道Sting介导的IFN-I参与放疗抗拒。我们发现EGFRm NSCLC中Sting、ISGs的mRNA水平升高。放疗联合EGFR-TKI诱导胞质DNA产生。由此提出本课题假说：放疗联合EGFR-TKI激活胞质DNA-Sting-IFN通路，IFN-I激活STAT1诱导细胞内源性抗拒，诱导PD-L1、IDO表达及MDSC聚集促进抑制性免疫，从而诱导放疗及EGFR-TKI治疗抗拒。研究通过建立脑转移动物模型，采用免疫荧光、流式、qRT-PCR、WB等技术，在体内、体外探讨胞质DNA-Sting-IFN通路是否参与放疗联合EGFR-TKI治疗抗拒，以及该通路是否通过诱导细胞内源性抗拒、免疫抑制性抗拒导致治疗抵抗的。研究结果有望为改善EGFRm NSCLC脑转移预后提供新靶点。

Radiotherapy combined with EGFR-TKI improved survival in patients with brain metastasis from EGFR mutant NSCLC patients, however, relapse occurred inevitable. Studies reported that Sting signaling induce the release of IFN-I and partially contribute to radio-resistance. Our previous study showed radiation combined with EGFR-TKI significantly increase the production of cytoplasmic DNA and micronucleus, both of which induce the transcription of interferon through Sting signaling. Besides, we have exploited the RNA-sequencing data of NSCLC from the TCGA, and the results showed that the expression of Sting gene TMEM173 and interferon-stimulated genes (ISGs) is significantly elevated in EGFRm NSCLC compared with that in EGFR wild type NSCLC. A similar trends is observed in NSCLC cell lines from CCLE. Based on these results, we proposed that radiotherapy and EGFR-TKI active the cytoplasmic DNA - Sting - interferon signaling, IFN-I influence the treatment sensitivity by stimulating the immunosuppressive microenvironment and enhancing the cell intrinsic radio-resistance. By establishing syngenetic brain metastasis tumor model, and with the following methods, such as immunofluorescence, flow cytometry, qRT-PCR and WB, we will detect whether cytoplasmic DNA - Sting signaling contribute to treatment resistance in radiotherapy and EGFR-TKI both in in vivo and in vitro, the influence of interferon on the immunosuppressive microenvironment and cell intrinsic radio-sensitivity will also be detected. The results of this study might provide a new target in the treatment of brain metastasis from NSCLC.