Mutations in CTNNB1 are present in 30% of cases of HCC, most of which present a "cold" immune phenotype, characterised by an absence of immune cell infiltration and resistance to immunotherapy. However, a previous study by the same group had already showed that a third of HCC cases with mutations in CTNNB1 show a "hot" immune profile, with the presence of immune cells and a response to immune checkpoint inhibitors. The molecular mechanisms responsible for this difference were unknown.
A new functional classification of mutations
The study has systematically analysed the impact of 342 genetic variants located in exon 3 of the CTNNB1 gene, where most of the mutations described are concentrated. The research team evaluated the ability of each of these variants to activate the WNT/β-catenin signalling pathway, and determine the impact on the immune profile. To do this, the researchers used an experimental CRISPR-based genome-editing strategy which allows exhaustive evaluation of the functional effect of all possible variants.
The results have enabled classification of CTNNB1 mutations into two large groups:
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Strong mutations, which cause intense activation of the WNT/β-catenin pathway, generating an immunosuppressive environment that prevents immune cells from entering the tumour, making it more insensitive to immunotherapy.
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Weak mutations, which activate the pathway to a limited extent and allow immune cells to infiltrate the tumour, which is associated to a better response to immunotherapy.
This classification has been validated in 124 samples from patients with HCC, confirming that the intensity of activation of the WNT/β-catenin pathway is a determining factor in the response to immunotherapy. Although the study focuses on HCC, the results are also relevant for other solid tumours with mutations in CTNNB1, such as endometrial, colon and central nervous system tumours. Furthermore, this study constitutes a resource of reference for interpreting the functional diversity of these mutations in different types of cancers.
A step towards precision medicine
This study not only provides a molecular explanation to variability in the response to immunotherapy in HCC, it also provides a tool for identifying patients that can reap the most benefit from these treatments. Furthermore, the results could have relevant implications in the development of new drugs aimed at modulating the WNT/β-catenin pathway.
The study involved the participation of various researchers from the IDIBAPS Translational Research in Hepatic Oncology group as co-authors of the study, including Agavni Mesropian, Albert Gris-Oliver, Roser Pinyol and Josep M. Llovet, leader of the IDIBAPS group.
“This discovery opens the door to personalised medicine strategies for hepatocellular carcinoma. Knowing the type of β-catenin mutation can help predict the response to immunotherapy and to design more effective therapeutic combinations,” highlights Llovet, chair professor of Medicine at the UB, ICREA professor and chair professor of Medicine at the Icahn School of Medicine at Mount Sinai,
For her part, Pinyol highlights: “We have demonstrated that not all mutations in CTNNB1 are the same. This information is key for stratifying patients and optimising treatments, especially in a context where immunotherapy is an increasingly relevant option.”
Study of reference
Krishna, A., Meynert, A., Dolt, K.S. et al. Mutational scanning reveals oncogenic CTNNB1 mutations have diverse effects on signaling. Nat Genet (2026). https://doi.org/10.1038/s41588-025-02496-5
