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Mechanistically, elevated cholesterol levels in these tumor-infiltrating CD8 + T cells trigger ER stress and activation of XBP1 signaling pathway which, in turn, leads to the expression of immune checkpoint molecules such as PD-1, natural killer cell receptor 2B4, metalloproteinase inhibitor 3 (TIM3) and lymphocyte activation gene 3 protein (LAG3) ( In hepatocellular carcinoma, tumor-secreted fibroblast growth factor 21 (FGF21) drives AKT activation in T cells, which stimulates mammalian target of rapamycin target complex 1 (mTORC1)