2. Academic Validation
  3. Intrinsic STING of CD8 + T cells regulates self-metabolic reprogramming and memory to exert anti-tumor effects

Intrinsic STING of CD8 + T cells regulates self-metabolic reprogramming and memory to exert anti-tumor effects

  • Cell Commun Signal. 2025 Feb 19;23(1):99. doi: 10.1186/s12964-025-02069-3.
Qiuli Xu # 1 2,  Xin Hua # 3,  Bingbing Li # 4,  Bei Jiang 4,  Jiajia Jin 2,  Ranpu Wu 1 2,  Yanli Gu 5,  Hao Xu 2 6,  Qinpei Cheng 7,  Suhua Zhu 2,  Fang Zhang 2 4,  Tangfeng Lv 8,  Yong Song 9 10
Affiliations

Affiliations

  • 1 School of Medicine, Southeast University, Nanjing, Jiangsu, 210002, China.
  • 2 Department of Respiratory and Critical Care Medicine, Affiliated Jinling Hospital, Nanjing, Jiangsu, 210002, China.
  • 3 Department of Geriatric Medicine, Affiliated Hospital of Medical School, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, China.
  • 4 Department of Respiratory and Critical Care Medicine, Affiliated Jinling Hospital, School of Medicine, Nanjing University of Traditional Chinese Medicine Southeast University, #305 East Zhongshan Road, Nanjing, Jiangsu, 210002, China.
  • 5 Department of Respiratory and Critical Care Medicine People's Hospital, Nanjing Medical University, Huai'an, Jiangsu, China.
  • 6 Nanjing Medical University, Nanjing, Jiangsu, 210002, China.
  • 7 Medical School of Nanjing University, Nanjing, Jiangsu, 210002, China.
  • 8 Department of Respiratory and Critical Care Medicine, Affiliated Jinling Hospital, School of Medicine, Nanjing University of Traditional Chinese Medicine Southeast University, #305 East Zhongshan Road, Nanjing, Jiangsu, 210002, China. TangfengLv7210@nju.edu.cn.
  • 9 School of Medicine, Southeast University, Nanjing, Jiangsu, 210002, China. yong.song@nju.edu.cn.
  • 10 Department of Respiratory and Critical Care Medicine, Affiliated Jinling Hospital, Nanjing, Jiangsu, 210002, China. yong.song@nju.edu.cn.
  • # Contributed equally.
PMID: 39972350 DOI: 10.1186/s12964-025-02069-3
Abstract

Background: Our team has previously found that the stimulator of interferon genes (STING) plays a more significant anti-tumor role in host immune cells than in tumor cells. Although STING is necessary for CD8 + T cells to exert immunological activity, its effect on CD8 + T cells remains debatable. In this study, we used both in vitro and in vivo models to explore the metabolic effects of STING on CD8 + T cells.

Methods: Peripheral blood lymphocytes were procured from non-small cell lung Cancer (NSCLC) patients receiving anti-PD-1 therapy to investigate the correlation between STING expression levels, CD8 + T-cell subsets, and immunotherapy efficacy. STING knockout (STING-KO) mice were used for in vivo studies. RNA-seq, seahorse, flow cytometry, electron microscopy, qPCR, immunofluorescence, western blotting, and immunoprecipitation were performed to explore the underlying mechanisms of STING in regulating CD8 + T cell function.

Results: We discovered that the expression level of STING in immune cells exhibited a significant correlation with immunotherapy efficacy, as well as with the proportion of central memory CD8 + T cells. Moreover, we found that the loss of the STING gene results in a reduction in the number of mitochondria and a change in the metabolic pathway selection, thereby inducing excessive glycolysis in CD8 + T cells. This excessive glycolysis generates high levels of lactate, which further inhibits IFN-γ secretion and impacts memory T cell differentiation. Correcting the glycolysis disorder partially restored function and IFN-γ secretion, rescued the central memory CD8 + T subset, and improved immunotherapy in STING-KO mice. This provides a new treatment strategy for patients with low STING expression and a poor response to immunotherapy.

Conclusion: Intrinsic STING of CD8 + T cells affects their function through the HK2/Lactate/IFN-γ axis and affects memory differentiation by regulating glycolysis.

Keywords

CD8 + T cells; Glycolysis; Immunotherapy; Metabolic reprogramming; Non-small cell lung cancer; STING.

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