清华大学李艳梅团队报道了一种基于多价驱动STING低聚的口袋独立激动剂，piSTING。相关研究成果发表在2024年5月20日出版的《德国应用化学》。

干扰素基因刺激因子（STING）方法是先天免疫的有效治疗靶点。尽管人们努力开发模拟内源性STING配体环鸟苷一磷酸-腺苷一磷酸（cGAMP）的口袋依赖性小分子STING激动剂，但由于STING口袋的局限性，这些激动剂中的大多数在临床试验中显示出令人失望的结果。

该文中，研究人员开发了新的口袋非依赖性STING激活激动剂（piSTINGs），其通过多价驱动的寡聚作用来激活STING。此外，在治疗模型中，piSTING佐剂疫苗引发了显著的抗体反应并抑制了肿瘤生长。此外，基于piSTING的疫苗与aPD-1的组合显示出增强免疫检查点阻断（ICB）免疫疗法有效性的显著潜力。特别是piSTING可以加强STING方法在免疫治疗中的作用，加速STING激动剂的临床转化。

附：英文原文

Title: piSTING: A Pocket-Independent Agonist Based on Multivalency-Driven STING Oligomerization

Author: Shao-Hua Zhuo, Tian-Yang Wang, Lang Zhao, Jing-Yun Su, Jin-Jian Hu, Yu-Fen Zhao, Yan-Mei Li

Issue&Volume: 2024-05-20

Abstract: The stimulator of interferon genes (STING) pathway is a potent therapeutic target for innate immunity. Despite the efforts to develop pocket-dependent small-molecule STING agonists that mimic the endogenous STING ligand, cyclic guanosine monophosphate–adenosine monophosphate (cGAMP), most of these agonists showed disappointing results in clinical trials owing to the limitations of the STING pocket. In this study, we developed novel pocket-independent STING-activating agonists (piSTINGs), which act through multivalency-driven oligomerization to activate STING. Additionally, a piSTING-adjuvanted vaccine elicited a significant antibody response and inhibited tumour growth in therapeutic models. Moreover, a piSTING-based vaccine combination with aPD-1 showed remarkable potential to enhance the effectiveness of immune checkpoint blockade (ICB) immunotherapy. In particular, piSTING can strengthen the impact of STING pathway in immunotherapy and accelerate the clinical translation of STING agonists.

DOI: 10.1002/anie.202407037

Source: https://onlinelibrary.wiley.com/doi/10.1002/anie.202407037