Chronic stress drives liver cancer by impairing the hepatic kynurenine pathway and immune surveillance

Abstract

Psychological stress is increasingly linked to liver disease, but the underlying mechanisms remain unclear. Here we show that chronic stress disrupts a brain-liver circuit that impairs hepatic CD8⁺ T cell immunity and accelerates liver cancer progression. Using both oncogene-driven and carcinogen-driven liver cancer models in male mice, we find that psychological stress disrupts catecholamine/β2-adrenergic receptor (ADRB2) signalling, which suppresses the expression of quinolinate phosphoribosyl transferase (QPRT), an enzyme of the kynurenine pathway, in hepatocytes. QPRT loss diverts kynurenine metabolism away from nicotinamide adenine dinucleotide (NAD⁺) synthesis towards kynurenic acid (KA) accumulation. This shift results in mitochondrial impairment and reduced effector function of liver CD8⁺ T cells. We confirm that ADRB2/QPRT expression correlates with hepatic NAD⁺ and KA levels and with CD8⁺ T cell frequency and function in human liver tissues. Importantly, ADRB2/QPRT overexpression in hepatocytes, or nicotinamide administration, recovers CD8⁺ T cell function in stressed mice and reduces liver cancer progression. These findings identify a stress-responsive metabolic checkpoint in the liver that links the nervous system to immune surveillance and may be therapeutically targeted in liver cancers.