BCAT1抑制肿瘤相关巨噬细胞代谢基因的巴豆酸相关表观遗传调节，以对抗免疫抑制
BCAT1 inhibits crotonate-related epigenetic modulation of metabolic genes in tumor-associated macrophages to counter immunosuppression.
摘要(中文译文)
肝细胞癌（HCC）中异质性且具有免疫抑制作用的肿瘤微环境（TME）导致免疫治疗反应不佳。肿瘤相关巨噬细胞（TAM）是免疫抑制性TME的核心，但代谢程序如何调控TAM的促肿瘤功能仍不完全清楚。在此，我们鉴定出支链氨基酸转氨酶1（BCAT1）是TAM中限制肿瘤进展的代谢检查点。与野生型TAM相比，BCAT1缺陷型TAM细胞内巴豆酸酯增加，组蛋白H3赖氨酸14巴豆酰化增强，脂质代谢基因上调，并呈现免疫抑制表型。在HCC小鼠模型中，BCAT1缺陷型TAM加重肿瘤负荷并抑制CD8 T细胞介导的抗肿瘤免疫，而髓系特异性BCAT1过表达或过继转移BCAT1巨噬细胞可刺激抗肿瘤免疫反应并改善抗PD1治疗反应。总之，我们的数据支持BCAT1介导的巴豆酸酯依赖性表观遗传调控在HCC免疫抑制性TAM中的作用，并表明BCAT1巨噬细胞可作为增强免疫检查点阻断治疗的辅助治疗手段。
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.
如何引用
AMA
Weizhi Zhang, Shuhang Liang, Sitao Han, Qingrui Zha, Linmao Sun, Shengwei Tao, et al. BCAT1 inhibits crotonate-related epigenetic modulation of metabolic genes in tumor-associated macrophages to counter immunosuppression.. Nature communications. 2026; doi:10.1038/s41467-026-72814-w.
APA
Weizhi Zhang, Shuhang Liang, Sitao Han, Qingrui Zha, Linmao Sun, Shengwei Tao, et al (2026). BCAT1 inhibits crotonate-related epigenetic modulation of metabolic genes in tumor-associated macrophages to counter immunosuppression.. Nature communications. https://doi.org/10.1038/s41467-026-72814-w
GB/T 7714
Weizhi Zhang, Shuhang Liang, Sitao Han, Qingrui Zha, Linmao Sun, Shengwei Tao, et al. BCAT1 inhibits crotonate-related epigenetic modulation of metabolic genes in tumor-associated macrophages to counter immunosuppression.[J]. Nature communications, 2026 doi:10.1038/s41467-026-72814-w.
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