STING诱导免疫的突变景观，这一成果由瑞士洛桑联邦理工学院Andrea Ablasser小组经过不懈努力而取得。2026年6月24日出版的《自然》发表了这项成果。

在这里，课题组研究人员开发了一种大规模平行分析来系统地绘制STING的序列功能景观。通过分析单个氨基酸变体的需求，该团队确定了影响STING免疫刺激能力及其将配体识别转化为不同信号输出的能力的结构和功能决定因素。选择的STING过度活跃变体的低温电镜结构揭示了新的调控原理，决定了STING从无活性状态到信号能力状态的构象转变。

突变效应在整个功能领域广泛存在，可以使STING对天然配体2’3’-cGAMP敏感，或使干扰素诱导从非典型自噬中解耦，表明可以通过单点取代获得多种可能的反应。最后，他们的数据显示了自然发生的STING蛋白变异的临床和进化相关性。总的来说，这些发现定义了调节STING活性的分子原理，并绘制了其在免疫背景下的功能潜力图。

据悉，干扰素刺激因子基因（STING）是一种进化保守的免疫信号蛋白，在宿主防御、癌症、衰老和炎症中起关键作用。在STING的下游，I型干扰素、炎症细胞因子信号传导和非典型自噬是由一个多层机制控制的，该机制整合了配体诱导的结构转变、蛋白-蛋白相互作用和协调的细胞内运输。尽管其在免疫中的核心作用和作为治疗靶点的相关性，但控制细胞中STING （in）激活的序列元件仍未完全了解。

附：英文原文

Title: The mutational landscape of STING-induced immunity

Author: Zhang, Bing, Xu, Pengbiao, Meng, Yu, Gallay, Laure, Lestelle, Franois, Morel, Hlne, Frmond, Marie-Louise, Correia, Bruno E., Ablasser, Andrea

Issue&Volume: 2026-06-24

Abstract: Stimulator of interferon genes (STING) is an evolutionary conserved immune signalling protein with key roles in host defence, cancer, senescence and inflammation1,2,3. Downstream of STING, type I interferon, inflammatory cytokine signalling and non-canonical autophagy are governed by a multilayered mechanism integrating ligand-induced structural transitions, protein–protein interactions and coordinated intracellular trafficking4,5,6,7,8,9,10,11,12,13. Despite its central role in immunity and relevance as therapeutic target14, the sequence elements that govern STING (in)activation in cells remain incompletely understood. Here we developed a massively parallel assay to systematically chart the sequence-function landscape of STING. Profiling thousands of single amino-acid variants, we identified structural and functional determinants that shape the immunostimulatory capacity of STING and its ability to translate ligand recognition into distinct signalling outputs. Cryogenic-electron microscopy structures of select STING hyperactive variants revealed new regulatory principles dictating conformational transition from inactive to signalling-competent states of STING. Mutational effects are widespread across the functional landscape and can sensitize STING towards the natural ligand 2′3′-cGAMP15,16,17,18 or decouple interferon induction from non-canonical autophagy, demonstrating a diversity of possible responses that can be accessed through single point substitutions. Finally, our data showed the clinical and evolutionary relevance of naturally occurring STING protein variants. Collectively, these findings define molecular principles that tune STING activity and chart the landscape of its functional potential across immune contexts.

DOI: 10.1038/s41586-026-10685-3

Source: https://www.nature.com/articles/s41586-026-10685-3