Macrophage-specific BCAT1 deficiency drives lipid-associated immunosuppressive remodeling and promotes HCC progression

The heterogeneous and immunosuppressive tumor microenvironment (TME) remains one of the major factors to the poor immunotherapeutic response in hepatocellular carcinoma (HCC). Tumor-associated macrophages (TAMs) are central orchestrators of this suppressive niche, yet the metabolic programs regulating their pro-tumorigenic functions remain incompletely understood. Here, we identify branched-chain amino acid transaminase 1 (BCAT1) as a metabolic checkpoint in TAMs that constrains tumor progression. Deficiency of BCAT1 in TAMs induces metabolic reprogramming, elevating intracellular crotonate levels and promoting histone crotonylation, which epigenetically activates lipid metabolism programs. This shift promotes TAM polarization toward a lipid-associated, immunosuppressive phenotype that accelerates HCC progression primarily by suppressing CD8+ T cell-mediated antitumor immunity