Na2SX纳米晶体作为新型caspase-9抑制剂用于放射-免疫增效治疗及其机制研究

放射治疗是目前癌症治疗的主要方法之一，可激发系统性的抗肿瘤免疫应答，将其与免疫检查点阻断治疗相结合可显著抑制癌症转移，但是肿瘤免疫抑制性微环境限制了其治疗响应率。受caspase-9抑制的cGAS-STING信号通路是天然免疫系统的重要组成部分，其激活将提升抗肿瘤免疫治疗的响应性。因此，本项目设想构建多硫化钠（Na2Sx）纳米晶体，促进放疗激活的caspase-9过硫化失活，进而解除cGAS-STING通路的抑制，达到增效放疗-免疫治疗的目的。本项目将摸索Na2Sx纳米晶体的简易制备方式并对其理化性质进行细致研究；考察Na2Sx对肿瘤细胞的靶向递送及对caspase-9活性和cGAS-STING通路的影响；基于Na2Sx开展增效放疗-免疫治疗的研究。本项目通过开发纳米生物材料作为新型caspase-9抑制剂，将提高放射-免疫治疗响应性，为治疗转移性肿瘤提供具有潜在实用价值的新策略和方法。

Radiotherapy is one of the main methods in clinical cancer treatment, and can stimulate systemic anti-tumor immune response. Combining radiotherapy with immune checkpoint therapy can significantly inhibit cancer metastasis, but tumor immunosuppressive microenvironment limits its response rate. Caspase-9-inhibited cGAS-STING signaling pathway is an important part of innate immune system, and its activation will enhance the response of anti-tumor immunotherapy. Therefore, this project proposes to construct sodium polysulfide (Na2Sx) nanocrystals to promote the persulfidation and deactivation of radiotherapy-activated caspase-9, and then remove the inhibition of cGAS-STING pathway for enhanced radiotherapy-immunotherapy. In this project, we will explore the simple method to prepare Na2Sx nanocrystals and study its physical and chemical properties in detail, investigate tumor targeted delivery of Na2Sx and the effects on caspase-9 activity and cGAS-STING pathway, and study the enhanced radiotherapy-immunotherapy with Na2Sx nanocrystals. This project will improve the response of radiotherapy-immunotherapy through development of nano-biomaterials as a novel caspase-9 inhibitor, and provide strategies with potential practical value for the treatment of metastatic tumor.