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<p>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<sup>+</sup> T cell-mediated antitumor immunity, while myeloid-specific BCAT1 overexpression or adoptive transfer of BCAT1<sup>+</sup> 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<sup>+</sup> macrophages as an adjuvant treatment for enhancing immune checkpoint blockade therapy.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月11日

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  • Weizhi Zhang,
  • Shuhang Liang,
  • Sitao 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,
  • Jiabei Wang,
  • Lianxin Liu

摘要

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.