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

Tumors use various strategies for immune evasion. Understanding 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 an essential immune suppressor. We show that FGF21 is upregulated in multiple types of tumors and promotes tumor progression. FGF21 significantly disrupts CD8+T anti-tumor immune response by rewiring cholesterol metabolism of CD8+ T cells. We further reveal that FGF21 activates AKT-mTORC1- sterolregulatoryelementbindingprotein 1 (SREBP1) signal axis to enhance cholesterol biosynthesis in CD8+T cells. FGF21 knockdown or blockade of FGF21 by a neutralizing antibody attenuates AKT-mTORC1 signaling and subsequently decreases cholesterol content in CD8+T cells, thus restoring CD8+T cytotoxic function and robustly suppressing tumor growth. Our findings uncover FGF21 as a “secreted immune checkpoint” to restrict anti-tumor immunity and suggest its inhibition is a useful strategy for improving the efficacy of cancer immunotherapy. To investigate the effect of FGF21 on CD8+T cells, we constructed shNC/shFgf21 tumor cell lines and sorted shNC/shFgf21 MC38 tumor-infiltrating T cells for RNA seq.