Bile acids enrichment supports tumor aerobic glycolysis and establishes immunosuppressive microenvironment

Abstract Fast-growing solid tumors employ aerobic glycolysis to meet the demand balance of energy and anabolic growth and promote tumor immune evasion. The tumor microenvironment (TME) factors that support aerobic glycolysis have not been determined. Here, we show that microbiota-metabolized bile acids (BA) were highly enriched in melanoma and breast cancer. Depletion of bile acids suppresses tumor progression, increases T cell infiltration, and alleviates T cell exhaustion. Transcriptome analysis reveals that a lack of bile acid improves the expression of oxidative phosphorylation genes in vivo. Bile acids enrichment supports aerobic glycolysis via FXR-RARα interaction. Depletion of BA impairs the tumor's immune suppressive barrier and reduces the protein levels of FXR and RARα. Our study unveils that a mechanism of tumor progression modulated BA-RA signaling by FXR-RARα interaction and bile acid as a latent target, which suggests a possible way for tumor diagnosis and treatments.