Chronic Stress Sabotages Liver Immunity and Fuels Cancer Through Hidden Metabolic Switch

Psychological stress is widely associated with worse cancer outcomes, but the precise biological mechanisms have remained elusive. This study, published in Nature Metabolism, provides a compelling mechanistic account of how chronic stress actively undermines the liver's immune defenses and accelerates tumor growth.

Using both oncogene-driven and carcinogen-induced liver cancer models in male mice, researchers demonstrated that chronic psychological stress disrupts a brain-liver communication circuit. Stress elevates catecholamines, which act on β2-adrenergic receptors (ADRB2) in hepatocytes. This signaling suppresses expression of quinolinate phosphoribosyl transferase (QPRT), an enzyme that normally channels kynurenine metabolism toward NAD+ production.

When QPRT is lost, the kynurenine pathway is diverted, causing kynurenic acid (KA) to accumulate instead. This metabolic shift has a downstream immune consequence: CD8+ T cells in the liver suffer mitochondrial dysfunction and lose their effector capacity, leaving tumors poorly surveilled and free to progress.

Importantly, the team validated these findings in human liver tissue, showing that ADRB2 and QPRT expression levels correlate with hepatic NAD+ and KA concentrations, as well as CD8+ T cell frequency and function. This cross-species consistency strengthens the translational significance of the findings.

Therapeutically, overexpressing ADRB2 or QPRT in hepatocytes, or simply administering nicotinamide (a NAD+ precursor), restored CD8+ T cell function in stressed mice and meaningfully reduced liver cancer progression. These findings identify a targetable stress-responsive metabolic checkpoint and open the door to interventions — including widely available supplements — that could counteract stress-induced immune suppression in liver cancer patients. Larger studies in humans will be needed to confirm efficacy and safety.