2. Academic Validation
  3. SENP3 senses oxidative stress to facilitate STING-dependent dendritic cell antitumor function

SENP3 senses oxidative stress to facilitate STING-dependent dendritic cell antitumor function

  • Mol Cell. 2021 Mar 4;81(5):940-952.e5. doi: 10.1016/j.molcel.2020.12.024.
Zhilin Hu 1,  Xiao-Lu Teng 1,  Tianyu Zhang 2,  Xiaoyan Yu 1,  Rui Ding 1,  Jing Yi 3,  Liufu Deng 4,  Zhengting Wang 5,  Qiang Zou 6
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 3 Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 4 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. Electronic address: dengliufu@shsmu.edu.cn.
  • 5 Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: zhengtingwang@shsmu.edu.cn.
  • 6 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. Electronic address: qzou1984@sjtu.edu.cn.
PMID: 33434504 DOI: 10.1016/j.molcel.2020.12.024
Abstract

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.

Keywords

SENP3; STING; antitumor function; dendritic cells; oxidative stress.

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