PCK1 deficiency promotes MASH-HCC progression by 12-HETE-induced CD8+ T cell dysfunction

Hepatocyte-specific Pck1 knockout mice exhibited markedly increased tumorigenesis in dietary models and genetic models of spontaneous MASH-HCC, together with inhibited effector function of tumor-infiltrating CD8+ T cells. Mechanistically, PCK1 deficiency induces the accumulation of endogenous metabolite 12-hydroxyeicosatetraenoic acid (12-HETE), which can be taken up by CD8+ T cells and activate the p38 mitogen-activated protein kinase pathway, ultimately leading to CD8+ T cells dysfunction.

Notably, PCK1 restoration or 12-HETE inhibition combined with anti-PD1 treatment increases the antitumor capability of CD8+ T cells and suppresses MASH-HCC development. This study reveals the pivotal role of the hepatic cell-intrinsic enzyme PCK1 in mediating CD8+ T cell dysfunction via 12-HETE-p38 signaling in MASH-HCC. PCK1 could be a metabolic checkpoint to enhance the efficacy of anti-PD1 immunotherapy in MASH-HCC.