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 4

Glycolysis potentiates STING-dependent DC antitumor function.

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Glycolysis potentiates STING-dependent DC antitumor function. (A and B) ...
(A and B) ELISA analysis of BMDCs treated with 2-DG (1 mM; A) or DCA (10 mM; B) overnight and then stimulated with cGAMP for 8 hours. (C) MC38 tumor growth of WT mice transferred with cGAMP-stimulated BMDCs. BMDCs were labeled with CTV following 2-DG (1 mM) treatment for 8 hours. 2-DG–pretreated BMDCs were then stimulated with cGAMP for 4 hours. MC38 tumor-bearing WT mice were injected s.c. adjacent to the tumor with 2 × 106 cGAMP-stimulated DCs on days 3 and 6 after tumor injection (n = 8). (D) The numbers of CTV+ DCs in the draining lymph nodes and tumors from mice from C on day 8 after tumor inoculation (n = 4). (E) The numbers of tumor-infiltrating CD4+ and CD8+ T cells from mice from C on day 14 after tumor inoculation (n = 4). (F and G) Flow cytometry analysis of tumor-infiltrating CD4+ and CD8+ T cells (F) or F4/80+ macrophages (G) from mice from C on day 14 after tumor inoculation. (H) Tumor growth of MC38 tumor-bearing WT mice transferred with cGAMP-stimulated DCs. BMDCs were pretreated with DCA (10 mM) for 8 hours and then stimulated with cGAMP for 4 hours. MC38 tumor-bearing WT mice were injected s.c. adjacent to the tumor with 2 × 106 cGAMP-stimulated DCs on days 3 and 6 after tumor injection (n = 8). (I and J) Flow cytometry analysis of tumor-infiltrating CD8+ and CD4+ T cells of the mice from H. Representative data are shown from 2 (C–J) and 3 (A and B) independent experiments. Data are shown as the mean ± SEM. Statistical analysis was performed using 1-way ANOVA (A, B, D–G, and J) and 2-way ANOVA (C and H); *P < 0.05; **P < 0.01.