Bile acid retention impairs tumoral antigen presentation and intrinsic tumor suppression in MASH-HCC.

Metabolic reprogramming enables tumor cells to evade immune surveillance, yet the mechanisms linking specific metabolic alterations to immune evasion remain incompletely understood. We found that in metabolic dysfunction-associated steatohepatitis (MASH)-related hepatocellular carcinoma (HCC) cells, aberrant accumulation of bile acids impairs the NOD-like receptor family CARD domain containing 5-mediated major histocompatibility complex class I antigen presentation pathway, thereby leading to loss of antigenicity in tumor cells. Bile acid retention in tumor cells results primarily from the downregulation of the efflux pump ABCB11, driven by G protein-coupled receptor 120-mediated FXR suppression under lipid-rich conditions. Furthermore, genetic inactivation of NLRC5 abolishes the recovery of MHC-I expression and antitumor immunity upon bile acid reduction. Treatment with Tropifexor, a potent selective FXR agonist, synergizes with immune checkpoint blockade, significantly reducing tumor burden and potentiating the intratumoral adaptive immune response in mice. Thus, we reveal that intracellular bile acid accumulation suppresses both tumor antigenicity and intrinsic antitumor immunity. This insight provides a therapeutic target for improving immunotherapy outcomes in MASH-HCC.