立体定向放射治疗联合免疫检测点抑制剂的放射-免疫远隔效应，极具临床价值却又可遇不可求，其内在机制亟需强化突破。我们建立放射-免疫远隔效应模型并生物信息学挖掘MSH3/PRKDC协同致死作用，鉴于该协同致死效应显著提升肿瘤免疫原性，提出科学假说：MSH3/PRKDC协同致死具备强化免疫原性坏死的必要条件及强化T细胞功能的充分条件，从而增强放射-免疫远隔效应。本项目拟从细胞水平、基因敲除小鼠、分子水平多层次正反两方向确证MSH3/PRKDC协同致死效应；以自发性肺鳞癌模型检测MSH3/PRKDC协同致死诱导放射免疫原性死亡，并验证协同致死诱导T细胞活化和杀伤效应；利用双人源化B-NDG人源肺癌模型进行临床前研究，以期阐明MSH3/PRKDC协同致死增强肺癌放射-免疫远隔效应的作用与机制。研究结果对于突破放射-免疫远隔效应的瓶颈提供新思路，具有重要的理论意义和应用前景。

The radio-immunotherapy abscopal effect induced by stereotactic body radiotherapy (SBRT) combined with immune checkpoint inhibitors (ICIs) is of great clinical value. However, the underlying mechanism remains unclear and needs to be elucidated urgently. Previously, we have established a radio-immunotherapy abscopal effect model and revealed the synthetic lethal effects of MSH3/PRKDC using bioinformatics approaches. Based on the fact that the synthetic lethality significantly enhanced tumor immunogenicity, we hypothesize that MSH3/PRKDC synthetic lethality is possibly necessary for promoting radio-immunogenic necrosis and sufficient for improving T cell functions, thus enhancing the radio-immunotherapy abscopal effect. This project plans to confirm the synthetic lethal effect of MSH3/PRKDC at in vitro, in vivo and molecular levels by crossover experiments; and then the spontaneous lung squamous cell carcinoma model will be used to detect the immunogenic cell death induced by MSH3/PRKDC synthetic lethality, and the activation and killing effect of T cells induced by synthetic lethal be verified; finally, preclinical investigation will be carried out using a model of B-NDG human lung cancer to clarify the enhancing effects of MSH3/PRKDC synthetic lethality on radio-immunotherapy abscopal effect in lung cancer and the underlying mechanism. The results may provide new insights into the ways to improve radio-immunotherapy abscopal effect, which has theoretical significance and applicable implications.