免疫系统
抑制器
生物
CD8型
新陈代谢
FGF21型
细胞生物学
细胞毒性T细胞
细胞代谢
免疫学
生物化学
基因
成纤维细胞生长因子
受体
体外
作者
Cegui Hu,Quan Wen,Xiang Li,Zhikun Ning,Jiang Liu,Sumiya Dalangood,Hanjun Li,Xiang Yu,Zhen Zong,Zhenke Wen,Jun Gui
标识
DOI:10.1016/j.cmet.2024.01.005
摘要
Tumors employ diverse strategies for immune evasion. Unraveling the mechanisms by which tumors suppress anti-tumor immunity facilitates the development of immunotherapies. Here, we have identified tumor-secreted fibroblast growth factor 21 (FGF21) as a pivotal immune suppressor. FGF21 is upregulated in multiple types of tumors and promotes tumor progression. Tumor-secreted FGF21 significantly disrupts anti-tumor immunity by rewiring cholesterol metabolism of CD8+T cells. Mechanistically, FGF21 sustains the hyperactivation of AKT-mTORC1-sterol regulatory-element-binding protein 1 (SREBP1) signal axis in the activated CD8+T cells, resulting in the augment of cholesterol biosynthesis and T cell exhaustion. FGF21 knockdown or blockade using a neutralizing antibody normalizes AKT-mTORC1 signaling and reduces excessive cholesterol accumulation in CD8+T cells, thus restoring CD8+T cytotoxic function and robustly suppressing tumor growth. Our findings reveal FGF21 as a “secreted immune checkpoint” that hampers anti-tumor immunity, suggesting that inhibiting FGF21 could be a valuable strategy to enhance the cancer immunotherapy efficacy.
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