12-HETE suppresses CD8+ T cell effector function via p38 MAPK signaling in MASH-HCC

Here, we identify that loss of PCK1 promotes endogenous metabolite 12-hydroxyeicosatetraenoic acid (12-HETE) accumulation in MASH-HCC mouse models, which was responsible for inducing CD8+ T cells dysfunction in MASH-HCC.

Inhibition of 12-HETE accumulation improves the efficiency of anti-PD1 therapy in MASH-HCC mouse models. 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.