Cancer is a leading cause of death in every country of the world and hepatocellular carcinoma (HCC) is third in line in terms of mortality (Sung, 2021). In the past few years, immunotherapy with immune checkpoint inhibitors (ICIs) has become a common treatment route for HCC, but a large proportion of patients are resistant to such treatments.

One reason has turned out to be gain-of-function mutations in the gene encoding β-catenin (CTNNB1). This leads, among many effects, to defective recruitment of antigen-presenting dendritic cells and antigen-specific T-cells, thus resulting in immune escape and resistance to immunotherapy (Sia, 2017, Gallareta, 2019).

β-catenin is a protein with dual functions. As a subunit of the cadherin protein complex, it has a prominent role in cell-cell adhesion, but it is also an important intracellular transducer in the canonical Wnt-signaling pathway, which regulates numerous biological processes. In this pathway, activation of the Wnt-receptor complex leads to cytosolic accumulation of β-catenin and its subsequent translocation to the nucleus. In the nucleus, β-catenin interacts with and modulates the activity of transcription factors, leading to altered expression of various target genes. The cellular level of β-catenin is mostly controlled by its ubiquitination and proteosomal degradation, and many of the gain-of-function mutations seen in HCC prevents this destruction pathway, leading to accumulation and nuclear translocation of β-catenin without external stimulus of the Wnt-signaling pathway.

β-catenin has traditionally been seen as an undruggable target, but a recent study published in Nature Communications (Lehrich, 2025), demonstrated that RNAi-mediated β-catenin inhibition delivered by a lipid nanoparticle (LNP) is a promising way forward. Treatment with LNP-CTNNB1, either alone or in combination with an ICI, resulted in activation of the immune regulatory transcription factors IRF2 and POU2F1, restored immune signaling, and increased recruitment of T-cells.

Ulrika Axelsson