Glycolysis drives STING signaling to facilitate dendritic cell antitumor function

Activation of STING signaling in DCs promotes antitumor immunity. Aerobic glycolysis is a metabolic hallmark of activated DCs, but how the glycolytic pathway intersects with STING signaling in tumor-infiltrating DCs remains elusive. Here, we show that glycolysis drives STING signaling to facilitate...

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Published in:The Journal of clinical investigation 2023-04, Vol.133 (7), p.1-11
Main Authors: Hu, Zhilin, Yu, Xiaoyan, Ding, Rui, Liu, Ben, Gu, Chuanjia, Pan, Xiu-Wu, Han, Qiaoqiao, Zhang, Yuerong, Wan, Jie, Cui, Xin-Gang, Sun, Jiayuan, Zou, Qiang
Format: Article
Language:English
Subjects:
Acids
Analysis
Antitumor activity
Biomedical research
Bone marrow
Cancer therapies
Carcinoma, Non-Small-Cell Lung - genetics
Carcinoma, Non-Small-Cell Lung - pathology
Cell activation
Cells
Dendritic Cells
Evaluation
Glucose
Glucose metabolism
Glycolysis
Homeostasis
Humans
Hypoxia-inducible factor 1a
Immune response
Immunology
Immunotherapy
Kinases
Lung cancer
Lung cancer, Non-small cell
Lung Neoplasms - genetics
Lung Neoplasms - pathology
Lymphocytes
Metabolism
Non-small cell lung carcinoma
Phosphorylation
Physiological aspects
Prevention
Signal Transduction
Small cell lung carcinoma
Tumors
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Summary:Activation of STING signaling in DCs promotes antitumor immunity. Aerobic glycolysis is a metabolic hallmark of activated DCs, but how the glycolytic pathway intersects with STING signaling in tumor-infiltrating DCs remains elusive. Here, we show that glycolysis drives STING signaling to facilitate DC-mediated antitumor immune responses. Tumor-infiltrating DCs exhibited elevated glycolysis, and blockade of glycolysis by DC-specific Ldha/Ldhb double deletion resulted in defective antitumor immunity. Mechanistically, glycolysis augmented ATP production to boost STING activation and STING-dependent DC antitumor functions. Moreover, DC-intrinsic STING activation accelerated HIF-1α-mediated glycolysis and established a positive feedback loop. Importantly, glycolysis facilitated STING-dependent DC activity in tissue samples from patients with non-small cell lung cancer. Our results provide mechanistic insight into how the crosstalk of glycolytic metabolism and STING signaling enhances DC antitumor activity and can be harnessed to improve cancer therapies.
ISSN:1558-8238
0021-9738
1558-8238
DOI:10.1172/JCI166031