Key Laboratory of RNA Science and Engineering, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China; Department of Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, China.
Key Laboratory of RNA Science and Engineering, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China; School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
Immunity. 2024 May 14;57(5):1087-1104.e7. doi: 10.1016/j.immuni.2024.03.021. Epub 2024 Apr 18.
Macrophages are critical to turn noninflamed "cold tumors" into inflamed "hot tumors". Emerging evidence indicates abnormal cholesterol metabolites in the tumor microenvironment (TME) with unclear function. Here, we uncovered the inducible expression of cholesterol-25-hydroxylase (Ch25h) by interleukin-4 (IL-4) and interleukin-13 (IL-13) via the transcription factor STAT6, causing 25-hydroxycholesterol (25HC) accumulation. scRNA-seq analysis confirmed that CH25H subsets were enriched in immunosuppressive macrophage subsets and correlated to lower survival rates in pan-cancers. Targeting CH25H abrogated macrophage immunosuppressive function to enhance infiltrating T cell numbers and activation, which synergized with anti-PD-1 to improve anti-tumor efficacy. Mechanically, lysosome-accumulated 25HC competed with cholesterol for GPR155 binding to inhibit the kinase mTORC1, leading to AMPKα activation and metabolic reprogramming. AMPKα also phosphorylated STAT6 Ser564 to enhance STAT6 activation and ARG1 production. Together, we propose CH25H as an immunometabolic checkpoint, which manipulates macrophage fate to reshape CD8 T cell surveillance and anti-tumor response.
巨噬细胞对于将无炎症的“冷肿瘤”转化为炎症的“热肿瘤”至关重要。新出现的证据表明，肿瘤微环境（TME）中的胆固醇代谢物异常，但功能尚不清楚。在这里，我们通过转录因子 STAT6 发现白细胞介素 4（IL-4）和白细胞介素 13（IL-13）可诱导胆固醇-25-羟化酶（Ch25h）的表达，导致 25-羟胆固醇（25HC）积累。scRNA-seq 分析证实，CH25H 亚群在免疫抑制性巨噬细胞亚群中富集，并与泛癌种中的较低生存率相关。靶向 CH25H 可破坏巨噬细胞的免疫抑制功能，增加浸润 T 细胞的数量和激活，与抗 PD-1 联合使用可提高抗肿瘤疗效。在机制上，积累在溶酶体中的 25HC 与胆固醇竞争 GPR155 结合，从而抑制激酶 mTORC1，导致 AMPKα 激活和代谢重编程。AMPKα 还磷酸化 STAT6 Ser564，增强 STAT6 激活和 ARG1 产生。总之，我们提出 CH25H 作为一种免疫代谢检查点，它操纵巨噬细胞命运，重塑 CD8 T 细胞监测和抗肿瘤反应。
