One phylogenetically conserved mechanism that controls tissue homeostasis and embryonic development is the Wnt/β-catenin pathway. It is aberrantly activated in a variety of cancers, driving malignant transformation, therapeutic resistance, and metastatic dissemination. The pathway regulates tumorigenesis by stabilizing β-catenin, which in turn activates TCF/LEF-mediated transcription of target genes. Uncontrolled cell proliferation, the maintenance of cancer stem cells (CSCs), the epithelial-mesenchymal transition (EMT), and metabolic reprogramming are all facilitated by dysregulated Wnt/β-catenin signaling, while forming an immunosuppressive tumor microenvironment (TME) through impaired dendritic cell (DC) maturation, reduced cytotoxic T cell infiltration, and upregulation of PD-L1. Notably, interactions with other pathways such as PI3K/AKT, Notch, and TGF-β amplify oncogenic signals, complicating therapeutic targeting. Due to the complexity of the pathway, tumor heterogeneity, and compensatory feedback, the clinical translation of Wnt/β-catenin inhibitors remains challenging. Current strategies include targeted inhibitors and combination therapies with immune checkpoint inhibitors (ICIs). Preclinical studies have shown that Wnt pathway blockade can enhance immunotherapy effects by reversing immunosuppression in the TME, while nanotherapeutics and natural compound-based therapies show promise in overcoming chemoresistance. This review integrates current insights into Wnt/β-catenin regulation and its integration with other oncogenic networks, and outlines clinical translational strategies targeting this master regulator, providing new strategies to block tumor progression and improve treatment durability.
Finch et al. (Sun,) studied this question.