STING Agonists as Cancer Therapeutics.
STING Agonists as Cancer Therapeutics.
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激动剂作为癌症治疗剂。
DOI：
10.3390/cancers13112695
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发表时间：
2021-05-30
期刊：
影响因子：
5.2
通讯作者：
Luke JJ
中科院分区：
文献类型：
--
作者：
Amouzegar A;Chelvanambi M;Filderman JN;Storkus WJ;Luke JJ
免疫疗法已经彻底改变了癌症治疗领域，然而相当一部分患者没有应答。最近的努力集中在鉴定可以引发或增强抗肿瘤免疫应答的靶点。一种这样的新靶标是干扰素（IFN）基因的STING或刺激物，干扰素基因是诱导促炎细胞因子如I型IFN产生的内质蛋白。自从发现STING以来，已经在不同肿瘤的临床前和临床环境中测试了许多天然和合成STING激动剂。然而，第一代激动剂的结构不稳定性促使开发更稳定和有效的化合物。本综述将重点介绍STING激动剂的最新药理学类别、肿瘤靶向药物递送的新方法以及STING途径临床靶向的挑战。对癌症免疫疗法的内在和适应性抗性的询问已经确定缺乏抗原呈递和I型干扰素信号传导作为非T细胞发炎肿瘤和临床进展的生物标志物。大量的临床前研究已经涉及cGAS/干扰素基因刺激物（STING）途径，一种在针对肿瘤的宿主免疫应答中驱动I型干扰素和其他炎性细胞因子活化的细胞溶质DNA传感途径。STING途径也越来越多地被理解为具有其他抗肿瘤功能，例如通过支持三级淋巴样结构发育来调节脉管系统和增强适应性免疫。许多天然和合成的STING激动剂已经进入临床开发，第一代肿瘤内递送的环状二核苷酸显示出安全性，但仅具有适度的全身活性。开发更有效和选择性的STING激动剂以及允许肿瘤微环境中持续炎症的新型递送系统可能会增加对当前免疫治疗方法的响应率并克服获得性耐药性。在这篇综述中，我们将重点介绍STING靶向治疗的最新进展，并提供单独使用STING激动剂或与免疫检查点阻断或其他方法联合使用的临床开发和应用的最新进展。
Immunotherapies have revolutionized the field of cancer therapeutics, yet a substantial subset of patients fail to respond. Recent efforts have focused on identifying targets that could elicit or augment anti-tumor immune responses. One such novel target is STING or stimulator of interferon (IFN) genes, an endoplasmic protein that induces the production of pro-inflammatory cytokines such as type I IFNs. Since the discovery of STING, numerous natural and synthetic STING agonists have been tested in both pre-clinical and clinical settings in different tumors. However, the structural instability of first-generation agonists prompted the development of more stable and potent compounds. This review will highlight the latest pharmacologic classes of STING agonists, novel approaches for tumor-targeted drug delivery, and challenges in the clinical targeting of the STING pathway. The interrogation of intrinsic and adaptive resistance to cancer immunotherapy has identified lack of antigen presentation and type I interferon signaling as biomarkers of non-T-cell-inflamed tumors and clinical progression. A myriad of pre-clinical studies have implicated the cGAS/stimulator of interferon genes (STING) pathway, a cytosolic DNA-sensing pathway that drives activation of type I interferons and other inflammatory cytokines, in the host immune response against tumors. The STING pathway is also increasingly understood to have other anti-tumor functions such as modulation of the vasculature and augmentation of adaptive immunity via the support of tertiary lymphoid structure development. Many natural and synthetic STING agonists have entered clinical development with the first generation of intra-tumor delivered cyclic dinucleotides demonstrating safety but only modest systemic activity. The development of more potent and selective STING agonists as well as novel delivery systems that would allow for sustained inflammation in the tumor microenvironment could potentially augment response rates to current immunotherapy approaches and overcome acquired resistance. In this review, we will focus on the latest developments in STING-targeted therapies and provide an update on the clinical development and application of STING agonists administered alone, or in combination with immune checkpoint blockade or other approaches.
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DOI：
10.1073/pnas.1512832112
发表时间：
2015-12-15
影响因子：
11.1
作者：
Demaria, Olivier;De Gassart, Aude;Gilliet, Michel
通讯作者：
Gilliet, Michel
影响因子：
8.8
作者：
Corrales L;Glickman LH;McWhirter SM;Kanne DB;Sivick KE;Katibah GE;Woo SR;Lemmens E;Banda T;Leong JJ;Metchette K;Dubensky TW Jr;Gajewski TF
通讯作者：
Gajewski TF
影响因子：
7.3
作者：
Campisi M;Sundararaman SK;Shelton SE;Knelson EH;Mahadevan NR;Yoshida R;Tani T;Ivanova E;Cañadas I;Osaki T;Lee SWL;Thai T;Han S;Piel BP;Gilhooley S;Paweletz CP;Chiono V;Kamm RD;Kitajima S;Barbie DA
通讯作者：
Barbie DA
影响因子：
64.8
作者：
Cabrita, Rita;Lauss, Martin;Jonsson, Goran
通讯作者：
Jonsson, Goran
DOI：
10.1084/jem.20101158
发表时间：
2011-09-26
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Diamond MS;Kinder M;Matsushita H;Mashayekhi M;Dunn GP;Archambault JM;Lee H;Arthur CD;White JM;Kalinke U;Murphy KM;Schreiber RD
通讯作者：
Schreiber RD