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

作者：Weizhi Zhang, Shuhang Liang, Shuo Han, Qingrui Zha, Linmao Sun, Shengwei Tao, Yunguang Zhang, Junhui Chu, Qi Chu, Ning Zhang, Kun Ma, Yufeng Liu, Tianming Cui, Xuetian Gu, Cheng Cheng, Xinyu Guo, Yumin Fu, Changjian Xing, Jiawei Duan, Yan Long, Dongdong Yang, Yi-Xiang Wang, Lianxin Liu · 发表于：Nature Communications · 年份：2026 · DOI：10.1038/s41467-026-72814-w · 研究领域：Immune cells in cancer、Ferroptosis and cancer prognosis、Cancer, Hypoxia, and Metabolism

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. Immunosuppressive tumor-associated macrophages (TAM) contribute to resistance to immune checkpoint blockade. Here, the authors propose BCAT1 to inhibit crotonate-mediated epigenetic reprogramming of tumor-associated macrophages, with BCAT1 loss promoting immune escape in hepatocellular carcinom...