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 CD8T cells. Mechanistically, FGF21 sustains the hyperactivation of AKT-mTORC1-sterol regulatory-element-binding protein 1 (SREBP1) signal axis in the activated CD8T 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 CD8T cells, thus restoring CD8T 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.

中文翻译：

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肿瘤分泌的 FGF21 通过重新连接 CD8+T 细胞的胆固醇代谢来充当免疫抑制剂

肿瘤采用多种策略来逃避免疫。揭示肿瘤抑制抗肿瘤免疫的机制有助于免疫疗法的发展。在这里，我们发现肿瘤分泌的成纤维细胞生长因子 21 (FGF21) 是一种关键的免疫抑制剂。 FGF21 在多种类型的肿瘤中表达上调并促进肿瘤进展。肿瘤分泌的 FGF21 通过重新连接 CD8T 细胞的胆固醇代谢来显着破坏抗肿瘤免疫。从机制上讲，FGF21 维持激活的 CD8T 细胞中 AKT-mTORC1-甾醇调节元件结合蛋白 1 (SREBP1) 信号轴的过度激活，导致胆固醇生物合成增强和 T 细胞耗竭。使用中和抗体敲低或阻断 FGF21 可使 AKT-mTORC1 信号转导正常化，并减少 CD8T 细胞中过多的胆固醇积累，从而恢复 CD8T 细胞毒性功能并强力抑制肿瘤生长。我们的研究结果表明，FGF21 是一种阻碍抗肿瘤免疫的“分泌性免疫检查点”，这表明抑制 FGF21 可能是增强癌症免疫治疗效果的一种有价值的策略。