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Activation of STING by cGAMP Regulates MDSCs to Suppress Tumor Metastasis via Reversing Epithelial-Mesenchymal
Hao Cheng1,2, Qiming Xu1,2, Xing Lu1,2
1Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
Abstract:
The role of cGAMP stimulating cGAS-cGAMP-STING-IRF3 pathway to inhibit tumor growth was well-established. Herein, the efficiency and pharmacological mechanism of cGAMP on regulating tumor metastasis was investigated. The effects of cGAMP regulating CD8+ T cells and myeloid-derived suppressor cells (MDSCs) in tumor microenvironment was explored. In this study, we found that cGAMP boosted STING signaling pathway to activate the production of IFN-γ from CD8+ T cells, and decreased the population of MDSCs in vivo. The metastasis in CT26 tumor bearing mice was inhibited by cGAMP via regulating EMT process. cGAMP played an important role in suppressing the production of reactive oxygen species (ROS) and nitric oxide (NO) from MDSCs, abolished the suppressive function of MDSCs to the T cells. All in all, the results indicated that the STING agonist cGAMP activated the production of IFN-γ from CD8+ T cells to suppress MDSCs in vivo.
Insights
Cyclic GMP-AMP (cGAMP) activates the STING pathway, boosting CD8+ T cells and reducing myeloid-derived suppressor cells (MDSCs) to inhibit tumor metastasis.
Area of Science:
- Immunology
- Cancer Biology
- Pharmacology
Background:
- The cyclic GMP-AMP (cGAMP)-STING-IRF3 pathway is known to inhibit tumor growth.
- Understanding cGAMP's role in regulating tumor metastasis and its interaction with immune cells is crucial.
Purpose of the Study:
- To investigate the efficiency and pharmacological mechanism of cGAMP in controlling tumor metastasis.
- To explore the effects of cGAMP on CD8+ T cells and myeloid-derived suppressor cells (MDSCs) within the tumor microenvironment.
Main Methods:
- In vivo studies using CT26 tumor-bearing mice.
- Analysis of STING signaling pathway activation.
- Assessment of CD8+ T cell activity and IFN-γ production.
- Quantification of MDSC populations and their function.
- Evaluation of epithelial-mesenchymal transition (EMT) process.
Main Results:
- cGAMP significantly boosted the STING signaling pathway, leading to increased IFN-γ production by CD8+ T cells.
- cGAMP treatment reduced the population of MDSCs in vivo.
- Tumor metastasis in CT26 tumor-bearing mice was inhibited by cGAMP through regulation of the EMT process.
- cGAMP suppressed reactive oxygen species (ROS) and nitric oxide (NO) production by MDSCs, thereby abolishing their suppressive effects on T cells.
Conclusions:
- cGAMP, a STING agonist, activates CD8+ T cells to produce IFN-γ.
- cGAMP effectively suppresses MDSCs in vivo, offering a potential therapeutic strategy against tumor metastasis.
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