Small molecules targeting the innate immune cGAS‒STING‒TBK1 signaling pathway.
Small molecules targeting the innate immune cGAS‒STING‒TBK1 signaling pathway.
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靶向先天免疫 cGAS–STING–TBK1 信号通路的小分子
DOI：
10.1016/j.apsb.2020.03.001
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发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Zhang A
中科院分区：
文献类型：
--
作者：
Ding C;Song Z;Shen A;Chen T;Zhang A
包括嵌合抗原受体T细胞和免疫检查点抑制剂（ICI）在内的多种癌症免疫疗法已被成功开发，以通过激发适应性抗肿瘤免疫来治疗各种癌症。特别地，检查点阻断方法已经取得了巨大的临床成功，如几种美国食品和药物管理局（FDA）批准的抗程序性死亡受体1/配体1或抗细胞毒性T淋巴细胞相关蛋白4抗体所证明的。然而，由于肿瘤免疫原性差，大多数癌症对这些ICI的临床应答率较低。事实上，干扰素基因cGAS结合激酶1（cGAS结合激酶TBK 1）轴的环鸟苷一磷酸-腺苷一磷酸合酶β刺激剂现在被认为是不同物种先天免疫应答中的主要信号传导途径。该通路的异常信号传导与多种疾病密切相关，包括自身炎症，病毒感染和癌症。从这个角度来看，我们提供了一个最新的审查的最新进展，小分子调节剂的发展，靶向cGAS抑制剂TBK 1信号通路及其临床前和临床使用作为一种新的免疫刺激疗法。同时，对临床候选人的亮点，局限性和挑战，以及在这一领域的未来发展方向也进行了讨论。此外，还讨论了靶向该信号传导轴的小分子抑制剂及其用于各种适应症的潜在治疗用途。cGAS激活TBK 1轴被认为是先天免疫应答中的主要信号传导途径，与多种疾病密切相关。本文综述了靶向cGAS抑制剂TBK 1信号通路的小分子调节剂的开发及其作为一种新型免疫刺激疗法的临床应用的最新进展。
Multiple cancer immunotherapies including chimeric antigen receptor T cell and immune checkpoint inhibitors (ICIs) have been successfully developed to treat various cancers by motivating the adaptive anti-tumor immunity. Particularly, the checkpoint blockade approach has achieved great clinic success as evidenced by several U.S. Food and Drug Administration (FDA)-approved anti-programmed death receptor 1/ligand 1 or anti-cytotoxic T lymphocyte associated protein 4 antibodies. However, the majority of cancers have low clinical response rates to these ICIs due to poor tumor immunogenicity. Indeed, the cyclic guanosine monophosphate-adenosine monophosphate synthase‒stimulator of interferon genes‒TANK-binding kinase 1 (cGAS‒STING‒TBK1) axis is now appreciated as the major signaling pathway in innate immune response across different species. Aberrant signaling of this pathway has been closely linked to multiple diseases, including auto-inflammation, virus infection and cancers. In this perspective, we provide an updated review on the latest progress on the development of small molecule modulators targeting the cGAS‒STING‒TBK1 signaling pathway and their preclinical and clinical use as a new immune stimulatory therapy. Meanwhile, highlights on the clinical candidates, limitations and challenges, as well as future directions in this field are also discussed. Further, small molecule inhibitors targeting this signaling axis and their potential therapeutic use for various indications are discussed as well. The cGAS‒STING‒TBK1 axis is appreciated as the major signaling pathway in innate immune response, which is closely linked to multiple diseases. This review summarizes the latest progress on the development of small molecule modulators targeting the cGAS‒STING‒TBK1 signaling pathway and their clinical use as a new immune stimulatory therapy.
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影响因子：
64.8
作者：
通讯作者：
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DOI：
10.1038/nri3921
发表时间：
2015-12
期刊：
Nature reviews. Immunology
影响因子：
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作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
120.1
作者：
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通讯作者：
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