BCAT1 inhibits crotonate-related epigenetic modulation of metabolic genes in tumor-associated macrophages to counter immunosuppression.

Abstract

The heterogeneous and immunosuppressive tumor microenvironment (TME) in hepatocellular carcinoma (HCC) contributes to poor immunotherapy responses. Tumor-associated macrophages (TAM) are central to the immunosuppressive TME, but how metabolic programs regulate TAM pro-tumorigenic functions remain incompletely understood. Here, we identify branched-chain amino acid transaminase 1 (BCAT1) as a metabolic checkpoint in TAMs constraining tumor progression. Compared with wild-type TAMs, BCAT1-deficient TAMs have increased intracellular crotonate, as well as enhanced histone H3 lysine 14 crotonylation, upregulated lipid metabolism genes and an immunosuppressive phenotype. In HCC mouse models, BCAT1-deficient TAMs aggravate tumor burden and suppress CD8⁺ T cell-mediated antitumor immunity, while myeloid-specific BCAT1 overexpression or adoptive transfer of BCAT1⁺ macrophages stimulates the antitumor immune response and improves anti-PD1 therapy responses. In summary, our data support a BCAT1-mediated regulation of crotonate-dependent epigenetic modulation of immunosuppressive TAMs in HCC, and indicate BCAT1⁺ macrophages as an adjuvant treatment for enhancing immune checkpoint blockade therapy.