Bile acids enrichment fuel tumor aerobic glycolysis and immune evasion via stabilizing FXR-RARα.

INTRODUCTION: Fast-growing solid tumors exhibit aerobic glycolysis to meet metabolic demands and evade immune surveillance. While the tumor microenvironment (TME) plays a crucial role in supporting this glycolytic phenotype, the contribution of host metabolites remains incompletely understood. METHODS: The role of bile acids (BAs) in tumor progression was evaluated using multiple mouse models, including C57BL/6J mice injected with B16 melanoma cells, BALB/c mice inoculated with 4T1 breast cancer cells, and MMTV-PyMT mice with spontaneous tumor development. To assess the impact of BA depletion, subjects were fed a 2% cholestyramine diet compared to a regular diet. The study employed various analytical techniques, including UPLC-MS to evaluate BA profiles, flow cytometry for immune cell analysis, and Seahorse extracellular flux analyzers to measure oxygen consumption and extracellular acidification rates. RESULTS: Here, we demonstrate that multiple bile acids (BAs) are significantly enriched in the TMEs of melanoma and breast cancer. Mechanistically, this BA enrichment drives tumor aerobic glycolysis and promotes immune evasion by modulating the interaction between the farnesoid X receptor (FXR) and retinoic acid receptor alpha (RARa). Depletion of BAs in vivo suppressed tumor progression, enhanced T cell infiltration, and alleviated T cell exhaustion, accompanied by transcriptome-wide shifts towardincreased expression of genes involved in oxidative phosphorylation. Furtherinvestigations revealed that BAs activate and stabilize the FXR-RARa complex,thereby upregulating glycolytic pathways and impairing anti-tumor immunity. Conversely, BA depletion reduced FXR/RARa protein levels and disrupted tumorimmune barrier function. DISCUSSION: These findings unveil a mechanism by which bile acids promote tumor progression by modulating tumor metabolism and the immune microenvironment through FXR-RARa signaling. Targeting the BA-FXR-RARa axiscould offer promising strategies for cancer therapy and diagnosis.