Department of Pharmacology and Chemical Biology, College of Basic Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Shanghai Institute of Immunology, College of Basic Medical Sciences & Central Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Cell Chem Biol. 2023 Jun 15;30(6):591-605.e4. doi: 10.1016/j.chembiol.2023.05.005. Epub 2023 May 31.
The cGAS-STING pathway has long been recognized as playing a crucial role in immune surveillance and tumor suppression. Here, we show that when the pathway is activated in a cancer-cell-autonomous response manner, it confers drug resistance. Targeted or conventional chemotherapy drugs promoted cytosolic DNA accumulation in cancer cells, activating the cGAS-STING pathway and downstream TBK1-IRF3/NF-κB signaling. This cancer cell-intrinsic response enabled the cells to counteract drug stress, allowing treatment resistance to be acquired and maintained. Blockade of stimulator of interferon genes (STING) signaling delayed and overcame resistance in models in vitro and in vivo. This finding uncovers an alternative face of cGAS-STING signaling other than the well-reported modulation of microenvironmental immune cells. It also implies a caution for the combination of STING agonist with targeted or conventional chemotherapy drug treatment, a strategy prevailing in current clinical trials.
cGAS-STING 通路长期以来一直被认为在免疫监视和肿瘤抑制中发挥着关键作用。在这里，我们表明，当该通路以癌症细胞自主反应的方式被激活时，它会赋予药物抗性。靶向或常规化疗药物促进了细胞质 DNA 在癌细胞中的积累，激活了 cGAS-STING 通路和下游 TBK1-IRF3/NF-κB 信号。这种癌症细胞内在的反应使细胞能够抵抗药物应激，从而获得并维持治疗抗性。干扰素基因刺激物 (STING) 信号的阻断在体外和体内模型中延迟和克服了耐药性。这一发现揭示了 cGAS-STING 信号的另一种替代形式，而不是众所周知的调节微环境免疫细胞。这也意味着在当前临床试验中流行的 STING 激动剂与靶向或常规化疗药物联合治疗需要谨慎。
Zotero 插件