Tumor-secreted FGF21 acts as an immune suppressor by rewiring cholesterol metabolism of CD8 < sup > + < /sup > T  cells

Cell Metab. 2024 Jan 23:S1550-4131(24)00006-8. doi: 10.1016/j.cmet.2024.01.005. Online ahead of print.ABSTRACTTumors 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.PMID:38309268 | DOI:10.1016/j.cmet.2024.01.005
Source: Cell Metabolism - Category: Cytology Authors: Source Type: research