Bile acids in the tumor immune microenvironment of hepatocellular carcinoma: Mechanisms of immunotherapy resistance and therapeutic opportunities.

Hepatocellular carcinoma (HCC) remains a major global health challenge due to its high mortality, with immunotherapy resistance representing a critical barrier to efficacy. Bile acids (BAs), beyond their metabolic role in cholesterol catabolism and lipid absorption, function as signaling molecules that regulate hepatic immunity through receptors such as farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5). This review examines how dysregulated BA metabolism reshapes the tumor immune microenvironment of HCC through effects on innate and adaptive immune cells, with consequences for CD8+ T-cell function, macrophage polarization, and stromal remodeling. It also highlights why the BA-microbiota-immunity axis has become a timely topic in the current immunotherapy era, particularly in the context of persistent resistance to immune checkpoint blockade. Current evidence supports the biological plausibility of BA-related biomarkers and therapeutic strategies, but most remain candidate or early translational rather than clinically validated. A better mechanistic and clinical understanding of BA-driven immune regulation may improve biomarker development and support more rational combination strategies for HCC immunotherapy.