Glycodeoxycholic acid inhibits hepatocellular carcinoma by driving M1 polarization of macrophages via the S1PR2–NF-κB–NLRP3 pathway

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.