细胞表面STING新亚型直接感受外源性cGAMP介导抗肿瘤免疫反应

STING在抗肿瘤免疫中发挥重要作用，目前STING激动剂已经成为肿瘤免疫治疗的研究热点。然而STING激动剂不能穿膜等缺点使得STING激动剂的研发陷入瓶颈。我们前期发现一种存在于细胞膜上的新型STING，其C端位于胞外区，进一步研究提示这种新型STING能直接感受细胞外cGAMP。结合相关文献我们提出：在细胞膜上存在一种嵌入膜内的STING亚型，其C端位于胞外，能直接被外源性cGAMP活化，从而激活IFN-β介导抗肿瘤免疫反应。本项目将以C端位于细胞外的STING新亚型为出发点，阐明外源性cGAMP直接激活STING新亚型诱导IFN-β的分子机制，探讨其在肿瘤免疫过程中发挥的作用。这种新型STING一旦被证实，将会克服STING激动剂不能穿膜等缺点带来的局限性，因此STING新亚型将成为肿瘤免疫治疗的重要药物靶点，同时为筛选新型STING激动剂提供高通量筛选平台，实现肿瘤治疗新突破。

Since STING plays a pivotal role in anti-tumor immunity, employing STING agonists have become a novel hot spot in tumor immunotherapy field. However, STING agonist development has fallen into a bottleneck due to the disadvantages of STING agonists cannot penetrate the membrane. We identified a non-canonical isoform of STING that is expressed on the cell surface with its C-terminal domain outside the cell and functions as the receptor for extracellular cGAMP. Combining the results with relative findings, we proposed that STING-N is a new isoform which is expressed on the cell surface with their C-terminal cGAMP binding sites outside the cell, an orientation necessary for activation by extracellular cGAMP. STING-N induces IFN production which promotes tumor immunity. In this project, we will focus on the new STING isoform with C-terminus outside the cell to elucidate exogenous cGAMP directly activate STING-N mediated tumor immune response and to explore its role in tumor immunity.Once this new STING isoform is confirmed, it will overcome the limitations of STING agonists and cell membrane penetration failure, greatly improving application efficiency of STING agonist. Therefore, cell surface STING-N isoform will become an important drug target, it is expected to establish an effective drug screening platform and achieve new breakthroughs in tumor therapy.