WNT-β-catenin signalling in hepatocellular carcinoma: from bench to clinical trials.

WNT-β-catenin activation is observed in around 50% of all patients with hepatocellular carcinoma (HCC), through either gain-of-function mutations in CTNNB1 (which encodes β-catenin) or loss-of-function mutations in AXIN1 or APC. Currently, first-line therapies for HCC are immune checkpoint inhibitor (ICI) combinations, and β-catenin-active HCCs have garnered increased attention due to their unique tumour immune microenvironment (TIME). This pathway is known to drive an immune-excluded TIME, but clinical investigations have provided a more nuanced perspective, with the emergence of a new 'immune-like' subclass of HCC that is paradoxically enriched for CTNNB1 mutations and has high levels of T cell infiltration. As such, patients and animal models with β-catenin activation treated with ICIs exhibit heterogeneous responses. Additionally, these tumours exhibit higher fatty acid oxidation to fuel tumour growth owing to a unique metabolic milieu shaped by zone 3 metabolism, which is a physiological function of WNT-β-catenin signalling in the liver lobule. Biomarkers to detect molecular subclasses of patients for targeted therapies are being developed. In this Review, we discuss advances in our understanding of the TIME and metabolism of β-catenin-active HCC, driven by in vitro and in vivo models and single-cell and spatial sequencing, and their implications for the treatment of a subset of HCCs using precision therapies against WNT-β-catenin signalling.