Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA.
Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA.
Trends Cell Biol. 2023 Mar;33(3):189-203. doi: 10.1016/j.tcb.2022.06.010. Epub 2022 Aug 2.
Pharmacology-based methods that promote antitumor immunity have the potential to be highly efficacious while avoiding the systemic cytotoxicity associated with traditional chemotherapies. Activation of type I interferon (IFN) signaling in antigen-presenting cell types [e.g., macrophages and dendritic cells (DCs)] is critical, if not essential, for inducing a tumor-specific adaptive immune response, including the activation of cytolytic CD8 T cells. In the context of promoting antitumor immunity, the cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway has emerged as a principal regulator of essential type I IFN signaling. As such, STING represents a highly attractive target for developing a first-in-class immunotherapy, albeit one with a potential for significant cell type- and downstream pathway-dependent on-target toxicities, as well as conceivable pharmacogenomic liabilities.
基于药理学的方法可以促进抗肿瘤免疫，具有高效的潜力，同时避免与传统化疗相关的全身细胞毒性。在诱导肿瘤特异性适应性免疫反应（包括细胞毒性 CD8 T 细胞的激活）中，抗原呈递细胞类型（例如巨噬细胞和树突状细胞（DCs））中 I 型干扰素（IFN）信号的激活至关重要，如果不是必需的话。在促进抗肿瘤免疫方面，环鸟苷酸-腺苷酸合酶/干扰素基因刺激物（cGAS/STING）途径已成为关键的 I 型 IFN 信号的主要调节剂。因此，STING 代表了开发一流免疫疗法的极具吸引力的靶点，尽管它具有潜在的显著细胞类型和下游途径依赖性的靶细胞毒性，以及可以想象的药物基因组学缺陷。
