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

ABSTRACT: Metabolic dysfunction-associated steatohepatitis-related hepatocellular carcinoma (MASH-HCC) has been reported to be less effective to immune checkpoint inhibitors, which may be associated with metabolic reprogramming of tumor cells and abnormal tumor microenvironment. Here, we aim to investigate the role of gluconeogenic enzyme phosphoenolpyruvate carboxykinase 1 (PCK1) in MASH-HCC and its interplay with the tumor microenvironment. Hepatocyte-specific phosphatase and tensin homolog (Pten) and Pck1 biallelic knockout mice were established to induce MASH-HCC. Single-cell RNA sequencing and multiparametric flow cytometry were performed to analyze the immune landscape alterations. PCK1 is downregulated in tumors tissues compared with adjacent non-cancerous tissues from patients with MASH-HCC. 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE302896 | GEO | 2026/08/26

REPOSITORIES: GEO