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 1

STING signaling–activated DCs exhibit enhanced glycolysis.

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STING signaling–activated DCs exhibit enhanced glycolysis. (A) Principal...
(A) Principal components analysis (PCA) of central carbon metabolome of bone marrow–derived DCs (BMDCs) stimulated with 2 μg/mL 2′3′-cGAMP (cGAMP) for 4 hours (n = 4). Each symbol represents data from an individual mouse. NT, nontreated; ST, cGAMP stimulated. (B and C) Heatmap analysis (B) and graph presentation (C) of differential metabolites in NT and ST groups from A. (D and E) Extracellular acidification rate (ECAR; n = 6; D) and oxygen consumption rate (OCR; n = 5; E) of BMDCs stimulated with 2 μg/mL cGAMP for 4 hours under basal (Bas) or maximum (Max) conditions. (F and G) ECAR (n = 5; F) and OCR (n = 6; G) of BMDCs stimulated with 40 μg/mL tumor DNA (Tu-DNA) for 4 hours under Bas or Max conditions. (H) Gene set enrichment analysis of the hallmark glycolysis pathway in the freshly isolated tumor-infiltrating DCs (Tu-DC) compared with that of splenic DCs (Spl-DC). DCs were isolated from MC38 tumor-bearing WT mice on day 14 after tumor injection. (I and J) ECAR (n = 5; I) and OCR (n = 3; J) of splenic and tumor-infiltrating DCs isolated from MC38 tumor-bearing WT mice on day 14 after tumor injection. Representative data are shown from 3 independent experiments in D–G, I, and J. Data are shown as the mean ± SEM. Statistical analysis was performed using 2-tailed Student’s t test; *P < 0.05; **P < 0.01.