Glycolysis drives STING signaling to facilitate dendritic cell antitumor function
Zhilin Hu, … , Jiayuan Sun, Qiang Zou
Zhilin Hu, … , Jiayuan Sun, Qiang Zou
Published February 23, 2023
Citation Information: J Clin Invest. 2023;133(7):e166031. https://doi.org/10.1172/JCI166031.
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Research Article Immunology Metabolism

Glycolysis drives STING signaling to facilitate dendritic cell antitumor function

Abstract

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.

Authors

Zhilin Hu, Xiaoyan Yu, Rui Ding, Ben Liu, Chuanjia Gu, Xiu-Wu Pan, Qiaoqiao Han, Yuerong Zhang, Jie Wan, Xin-Gang Cui, Jiayuan Sun, Qiang Zou

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Figure 5

Glycolysis promotes STING signaling via glycolytic ATP production.

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Glycolysis promotes STING signaling via glycolytic ATP production. (A an...
(A and B) Intracellular ATP of BMDCs stimulated with 2 μg/mL cGAMP (A) or 40 μg/mL Tu-DNA (B) for 4 hours. (C) Intracellular ATP of splenic DCs (Spl-DC) and tumor-infiltrating DCs (Tu-DC) isolated from WT mice inoculated s.c. with MC38 colon cancer cells at 14 days. (D and E) Intracellular ATP of BMDCs stimulated with 2 μg/mL cGAMP in the presence of streptolysin-O (SLO) and ATP for 2 hours. BMDCs were pretreated with 2-DG (1 mM; D) or DCA (10 mM; E) overnight and subsequently stimulated as indicated. (F) Intracellular ATP of WT and Ldha/b-DKO (DKO) BMDCs stimulated with 2 μg/mL cGAMP in the presence of SLO and ATP for 2 hours. (G and H) Immunoblot analysis of indicated proteins in whole-cell lysates of BMDCs stimulated with 2 μg/mL cGAMP in the presence of SLO and ATP for 2 hours. BMDCs were pretreated with 2-DG (1 mM; G) or DCA (10 mM; H) overnight and subsequently stimulated as indicated. (I) Immunoblot analysis of indicated proteins in whole-cell lysates of WT and Ldha/b-DKO BMDCs stimulated with 2 μg/mL cGAMP in the presence of SLO and ATP for 2 hours. The numbers indicate the relative densities of indicated protein bands normalized to β-actin. Representative data are shown from 3 independent experiments. Data are shown as the mean ± SEM. Statistical analysis was performed using 2-tailed Student’s t test (A–C) and 1-way ANOVA (D–F); *P < 0.05; **P < 0.01.