Prolonged activation of innate immune pathways by a polyvalent STING agonist.
Prolonged activation of innate immune pathways by a polyvalent STING agonist.
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DOI：
10.1038/s41551-020-00675-9
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发表时间：
2021-05
影响因子：
28.1
通讯作者：
Gao J
中科院分区：
文献类型：
--
作者：
Li S;Luo M;Wang Z;Feng Q;Wilhelm J;Wang X;Li W;Wang J;Cholka A;Fu YX;Sumer BD;Yu H;Gao J
干扰素基因刺激物 (STING) 是一种内质网跨膜蛋白，是传染病和癌症治疗的靶点。然而，小分子 STING 激动剂的早期临床试验显示其抗肿瘤功效有限且具有剂量限制性毒性。在这里，我们发现多价 STING 激动剂（一种带有叔胺 (PC7A) 的七元环的 pH 敏感聚合物）通过聚合物诱导形成 STING-PC7A 缩合物来激活先天免疫途径。与天然 STING 配体 2',3'-环状 GMP-AMP (cGAMP) 相比，PC7A 通过与不同于 cGAMP 结合袋的非竞争性 STING 表面位点结合，刺激促炎细胞因子的延长产生。 PC7A 诱导依赖于 STING 表达和 CD8+ T 细胞活性的抗肿瘤反应，PC7A 和 cGAMP 的组合在携带皮下肿瘤的小鼠以及切除的人类肿瘤和淋巴结中产生了协同治疗结果（包括激活 cGAMP 抗性 STING 变体）。通过聚合物诱导的 STING 缩合激活 STING 通路可能会提供新的治疗机会。多价 STING 激动剂通过形成 STING 缩合物来延长先天免疫途径的激活，并与 STING 配体 cGAMP 结合时在体内产生协同治疗结果。
The stimulator of interferon genes (STING) is an endoplasmic reticulum transmembrane protein that is a target of therapeutics for infectious diseases and cancer. However, early-phase clinical trials of small-molecule STING agonists have shown limited antitumour efficacy and dose-limiting toxicity. Here, we show that a polyvalent STING agonist—a pH-sensitive polymer bearing a seven-membered ring with a tertiary amine (PC7A)—activates innate-immunity pathways through the polymer-induced formation of STING–PC7A condensates. In contrast to the natural STING ligand 2′,3′-cyclic-GMP-AMP (cGAMP), PC7A stimulates the prolonged production of pro-inflammatory cytokines by binding to a non-competitive STING surface site that is distinct from the cGAMP binding pocket. PC7A induces antitumour responses that are dependent on STING expression and CD8+ T-cell activity, and the combination of PC7A and cGAMP led to synergistic therapeutic outcomes (including the activation of cGAMP-resistant STING variants) in mice bearing subcutaneous tumours and in resected human tumours and lymph nodes. The activation of the STING pathway through polymer-induced STING condensation may offer new therapeutic opportunities. A polyvalent STING agonist prolongs the activation of innate-immunity pathways through the formation of STING condensates, and leads to synergistic therapeutic outcomes in vivo when combined with the STING ligand cGAMP.
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影响因子：
38.3
作者：
Luo M;Wang H;Wang Z;Cai H;Lu Z;Li Y;Du M;Huang G;Wang C;Chen X;Porembka MR;Lea J;Frankel AE;Fu YX;Chen ZJ;Gao J
通讯作者：
Gao J
影响因子：
32.4
作者：
Jung, S;Unutmaz, D;Lang, RA
通讯作者：
Lang, RA
DOI：
10.1038/nri3921
发表时间：
2015-12
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
64.8
作者：
Li, Pilong;Banjade, Sudeep;Cheng, Hui-Chun;Kim, Soyeon;Chen, Baoyu;Guo, Liang;Llaguno, Marc;Hollingsworth, Javoris V.;King, David S.;Banani, Salman F.;Russo, Paul S.;Jiang, Qiu-Xing;Nixon, B. Tracy;Rosen, Michael K.
通讯作者：
Rosen, Michael K.
影响因子：
30.3
作者：
Dobbs N;Burnaevskiy N;Chen D;Gonugunta VK;Alto NM;Yan N
通讯作者：
Yan N