Glycodeoxycholic acid inhibits hepatocellular carcinoma by driving M1 polarization of macrophages via the
Mingxia Deng1, Jing Liu1, Li Zhang2
1Key Laboratory for Drug Evaluation and Clinical Research of Zhejiang Province, Department of Clinical Pharmacy, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
Background & Aims:
As liver-specific metabolites, bile acids could regulate antitumor immune responses and could represent a new therapeutic strategy for hepatocellular carcinoma (HCC).
Methods:
This study integrated metabolomics, transcriptomics, and immunofluorescence of clinical tissues (61 paired tumor and adjacent samples) and peripheral blood (serum from 59 patients with HCC and 19 healthy individuals) to identify differential bile acids and explore their correlations with clinicopathological features and immunity in HCC. Focusing on the identified bile acid glycodeoxycholic acid (GDCA), we elucidated its regulatory mechanisms in the tumor microenvironment (TME), especially M1 polarization of macrophages, and its roles in inhibiting HCC progression and enhancing the efficacy of immunotherapy.
Results:
GDCA was significantly reduced (p = 0.0026) in HCC tissues and was closely associated with adverse clinicopathological features, such as vascular invasion (p = 0.029) and advanced TNM stages (p = 0.014), as well as an immunosuppressive TME. Mechanistic studies revealed that GDCA activated M1 macrophages through the S1PR2-NF-κB-NLRP3 pathway, exerting antitumor immune effects. It could also synergize with anti-PD-1 antibodies to enhance anti-HCC efficacy.
Conclusions:
This study showed that the bile acid GDCA inhibited HCC progression by driving M1 macrophage polarization, suggesting targeting bile acids to reshape the tumor immune microenvironment as a viable strategy to enhance therapy.
Impact And Implications:
A specific bile acid, GDCA, is significantly reduced in liver cancer (HCC) tissue, with lower GDCA levels associating with adverse clinicopathological features and a weaker antitumor immune response. This study found that GDCA can reprogram tumor-associated macrophages into a tumor-fighting state by activating a specific molecular pathway (S1PR2-NF-κB-NLRP3). In animal models, restoring GDCA levels inhibited tumor growth and worked synergistically with anti-PD-1 immunotherapy. These findings reveal a new mechanism of immune regulation in HCC and suggest targeting bile acid metabolism as a promising strategy to enhance immunotherapy efficacy.
Insights
The bile acid glycodeoxycholic acid (GDCA) is reduced in liver cancer, hindering antitumor immunity. Restoring GDCA promotes M1 macrophage polarization, inhibiting HCC progression and enhancing immunotherapy.
Area of Science:
- Hepatocellular Carcinoma Research
- Immunometabolism
- Gastroenterology
Background:
- Bile acids, liver-specific metabolites, play a role in regulating antitumor immune responses.
- Bile acids represent a potential therapeutic strategy for hepatocellular carcinoma (HCC).
Purpose of the Study:
- To identify differential bile acids in HCC.
- To explore correlations between bile acids, clinicopathological features, and immunity in HCC.
- To elucidate the mechanisms of glycodeoxycholic acid (GDCA) in regulating the tumor microenvironment (TME) and HCC progression.
Main Methods:
- Integrated metabolomics, transcriptomics, and immunofluorescence on clinical HCC tissues and serum.
- Analysis of differential bile acids and their association with clinicopathological features and immune profiles.
- Mechanistic studies on GDCA's role in macrophage polarization and HCC inhibition.
Main Results:
- GDCA was significantly reduced in HCC tissues and associated with adverse clinicopathological features and an immunosuppressive TME.
- GDCA activated M1 macrophages via the S1PR2-NF-κB-NLRP3 pathway, exerting antitumor effects.
- GDCA synergized with anti-PD-1 antibodies to enhance anti-HCC efficacy in preclinical models.
Conclusions:
- GDCA inhibits HCC progression by promoting M1 macrophage polarization.
- Targeting bile acid metabolism to reshape the TME is a viable strategy for enhancing HCC therapy.
- GDCA represents a promising therapeutic target for hepatocellular carcinoma.
