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Acetoacetate-GPR43 axis epigenetically silences IL-6/CSF1 to restrict TAMs-driven metastatic lung cancer
Shuying Yuan1, Biying Xiao1, Shuaishuai Ni1
1Cancer Institute of Traditional Chinese Medicine, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China.
Journal of Translational Medicine
|August 13, 2026
Summary
Restoring acetoacetate levels combats lung cancer metastasis by reducing tumor-associated macrophages. This metabolic-epigenetic-immune axis involves acetoacetate signaling through GPR43 to suppress inflammation and limit cancer spread.
Area of Science:
- Metabolic regulation of cancer immunity
- Epigenetic mechanisms in metastasis
- Tumor microenvironment modulation
Background:
- Metastasis is a leading cause of cancer mortality, with lung metastasis being particularly challenging.
- Tumor-associated macrophages (TAMs) are key players in establishing metastatic niches.
- The influence of host ketone bodies on the immune microenvironment in metastasis is not well understood.
Purpose of the Study:
- To investigate the role of acetoacetate, a ketone body, in lung cancer metastasis.
- To elucidate the mechanisms by which acetoacetate influences the tumor microenvironment and immune cells.
- To identify potential therapeutic targets for metastatic lung cancer based on metabolic-immune interactions.
Main Methods:
- Pan-cancer gene expression analysis to study enzymes in acetoacetate metabolism.
- Murine models of metastatic lung cancer to assess acetoacetate's role.
- Flow cytometry, immunohistochemistry, molecular modeling, and various molecular assays to investigate acetoacetate-GPR43 interaction and downstream epigenetic regulation of cytokine genes (IL-6, CSF1).
Main Results:
- Lung cancer is associated with acetoacetate deficiency due to suppressed ketogenesis and increased ketolysis.
- Restoring acetoacetate levels significantly reduced lung cancer metastasis and TAM infiltration.
- Acetoacetate acts as a ligand for GPR43, mediating anti-metastatic effects by increasing MAT2A and S-adenosylmethionine, leading to DNA hypermethylation and silencing of pro-inflammatory cytokine genes (IL-6, CSF1).
Conclusions:
- A novel metabolic-epigenetic-immune axis is identified, where acetoacetate reprograms monocyte epigenetics via GPR43 signaling to suppress pro-metastatic inflammation.
- The acetoacetate-GPR43 axis presents a potential therapeutic strategy for metastatic lung cancer.
- This axis offers insights into overcoming limitations of current TAM-targeted therapies.
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