Shanghai Institute of Immunology, Department of Immunology and Microbiology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Mol Cell. 2021 Mar 4;81(5):940-952.e5. doi: 10.1016/j.molcel.2020.12.024.
STING-dependent cytosolic DNA sensing in dendritic cells (DCs) initiates antitumor immune responses, but how STING signaling is metabolically regulated in the tumor microenvironment remains unknown. Here, we show that oxidative stress is required for STING-induced DC antitumor function through a process that directs SUMO-specific protease 3 (SENP3) activity. DC-specific deletion of Senp3 drives tumor progression by blunting STING-dependent type-I interferon (IFN) signaling in DCs and dampening antitumor immune responses. DC-derived reactive oxygen species (ROS) trigger SENP3 accumulation and the SENP3-IFI204 interaction, thereby catalyzing IFI204 deSUMOylation and boosting STING signaling activation in mice. Consistently, SENP3 senses ROS to facilitate STING-dependent DC activity in tissue samples from colorectal cancer patients. Our results reveal that oxidative stress as a metabolic regulator promotes STING-mediated DC antitumor immune responses and highlights SENP3 as an overflow valve for STING signaling induction in the metabolically abnormal tumor microenvironment.
STING 依赖的树突状细胞 (DC) 胞质 DNA 感应引发抗肿瘤免疫反应，但 STING 信号在肿瘤微环境中的代谢调节仍不清楚。在这里，我们表明氧化应激是通过一种过程来诱导 STING 诱导的 DC 抗肿瘤功能所必需的，该过程指导 SUMO 特异性蛋白酶 3 (SENP3) 的活性。通过削弱 DC 中 STING 依赖性 I 型干扰素 (IFN) 信号和抑制抗肿瘤免疫反应，DC 特异性缺失 Senp3 驱动肿瘤进展。DC 衍生的活性氧 (ROS) 触发 SENP3 积累和 SENP3-IFI204 相互作用，从而催化 IFI204 的去 SUMO 化，并在小鼠中增强 STING 信号激活。一致地，SENP3 感应 ROS 以促进结直肠癌患者组织样本中 STING 依赖性 DC 活性。我们的结果表明，氧化应激作为一种代谢调节剂促进了 STING 介导的 DC 抗肿瘤免疫反应，并强调了 SENP3 作为代谢异常肿瘤微环境中 STING 信号诱导的溢流阀的作用。
