Wnt/β-catenin Signaling in Hepatocellular Carcinoma: A Major Context-Dependent Contributor to Resistance to Tyrosine Kinase Inhibitors and Immune Checkpoint Inhibitors

Hepatocellular carcinoma (HCC), accounting for nearly 90% of primary liver cancers, remains a major global health challenge due to late diagnosis and therapy resistance. Up to 50% of cases exhibit aberrant activation of the canonical Wnt/β-catenin pathway, driven by CTNNB1 mutations or inactivating alterations in AXIN1, APC, or ZNRF3, which are mutually exclusive. This hyperactivation has complex implications: it has been associated with drug resistance, larger tumors, epithelial-mesenchymal transition, vascular invasion, cancer stemness, and immune evasion, yet in some contexts, it correlates with a less aggressive, well-differentiated phenotype and improved survival. This heterogeneity highlights the need for further research to clarify its prognostic significance. This review explores recent mechanisms by which aberrant nuclear β-catenin accumulation fosters resistance to frontline tyrosine kinase inhibitors like sorafenib and lenvatinib through ferroptosis evasion, cancer stemness, and β-catenin stabilization. It also highlights how hyperactivated Wnt/β-catenin promotes an immunosuppressive "cold" tumor microenvironment, impairing immunotherapy efficacy. These include cytokine profile alterations, CD8+ T-cell exclusion, dendritic cell repression, and recruitment of immunosuppressive cells such as myeloid-derived suppressor cells, tumor-associated neutrophils, M2 macrophages, and regulatory T cells. Recent preclinical studies show that combining Wnt inhibitors with immunotherapy or tyrosine kinase inhibitors can reprogram the tumor microenvironment, restore ferroptosis sensitivity, eradicate cancer stem cells, enhance CD8+ T-cell infiltration, boost anti-tumor immunity, and overcome resistance with minimal side effects. Targeting the Wnt/β-catenin pathway offers a promising strategy to transform HCC treatment and improve outcomes by exploiting this pathway as a key therapeutic vulnerability.