中国科学院分子细胞科学卓越创新中心王红艳等研究人员合作发现，25-羟基胆固醇调节溶酶体AMP激酶的激活和代谢重编程来改造免疫抑制巨噬细胞。2024年4月18日，国际知名学术期刊《免疫》在线发表了这一成果。

研究人员发现白细胞介素-4（IL-4）和白细胞介素-13（IL-13）通过转录因子STAT6诱导胆固醇-25-羟化酶（Ch25h）的表达，导致25-羟基胆固醇（25HC）的积累。scRNA-seq分析证实，CH25H^hi亚群富集在免疫抑制巨噬细胞亚群中，并与泛癌中较低的生存率相关。靶向CH25H能削弱巨噬细胞的免疫抑制功能，从而提高浸润性T细胞的数量和活化，这与抗PD-1协同提高了抗肿瘤疗效。

从机制上讲，溶酶体蓄积的25HC与胆固醇竞争GPR155结合，抑制激酶mTORC1，导致AMPKα激活和代谢重编程。AMPKα还能使STAT6 Ser564磷酸化，从而增强STAT6的活化和ARG1的产生。综上所述，研究人员认为CH25H是一种免疫代谢检查点，它能操纵巨噬细胞的命运，从而重塑CD8⁺T细胞的监控和抗肿瘤反应。

据介绍，巨噬细胞是将非炎症性“冷肿瘤”转变为炎症性“热肿瘤”的关键。新的证据表明，肿瘤微环境（TME）中的胆固醇代谢物异常，且功能不明。

附：英文原文

Title: 25-Hydroxycholesterol regulates lysosome AMP kinase activation and metabolic reprogramming to educate immunosuppressive macrophages

Author: Jun Xiao, Shuang Wang, Longlong Chen, Xinyu Ding, Yuanhao Dang, Mingshun Han, Yuxiao Zheng, Huan Shen, Sifan Wu, Mingchang Wang, Dan Yang, Na Li, Chen Dong, Miao Hu, Chen Su, Weiyun Li, Lijian Hui, Youqiong Ye, Huiru Tang, Bin Wei, Hongyan Wang

Issue&Volume: 2024-04-18

Abstract: 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 factorSTAT6, causing 25-hydroxycholesterol (25HC) accumulation. scRNA-seq analysis confirmedthat CH25Hhi subsets were enriched in immunosuppressive macrophage subsets and correlated to lowersurvival rates in pan-cancers. Targeting CH25H abrogated macrophage immunosuppressivefunction to enhance infiltrating T cell numbers and activation, which synergized withanti-PD-1 to improve anti-tumor efficacy. Mechanically, lysosome-accumulated 25HCcompeted with cholesterol for GPR155 binding to inhibit the kinase mTORC1, leadingto AMPKα activation and metabolic reprogramming. AMPKα also phosphorylated STAT6 Ser564to enhance STAT6 activation and ARG1 production. Together, we propose CH25H as animmunometabolic checkpoint, which manipulates macrophage fate to reshape CD8+ T cell surveillance and anti-tumor response.

DOI: 10.1016/j.immuni.2024.03.021

Source: https://www.cell.com/immunity/abstract/S1074-7613(24)00142-0