Department of Pharmacology, Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Department of Pathology, Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Nat Biomed Eng. 2021 May;5(5):455-466. doi: 10.1038/s41551-020-00675-9. Epub 2021 Feb 8.
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.
干扰素基因刺激物 (STING) 是一种内质网跨膜蛋白，是治疗传染病和癌症的药物靶点。然而，小分子 STING 激动剂的早期临床试验显示出有限的抗肿瘤疗效和剂量限制毒性。在这里，我们表明，一种多价 STING 激动剂 - 一种带有叔胺的七元环的 pH 敏感聚合物（PC7A） - 通过聚合物诱导的 STING-PC7A 凝聚物的形成激活先天免疫途径。与天然 STING 配体 2'，3'-环鸟苷酸-AMP（cGAMP）相比，PC7A 通过结合不同于 cGAMP 结合口袋的非竞争性 STING 表面位点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，并且 PC7A 和 cGAMP 的组合导致携带皮下肿瘤和切除的人类肿瘤和淋巴结的小鼠产生协同治疗效果（包括激活 cGAMP 抗性 STING 变体）。通过聚合物诱导的 STING 凝聚物激活 STING 途径可能提供新的治疗机会。
