Wnt signaling and the tumor microenvironment: implications for cancer progression and therapeutics

The Wnt (Wingless/Integrated) signaling pathway is a highly conserved regulator of development, stem cell maintenance, and tissue homeostasis. Its dysregulation is a hallmark of cancer, driving uncontrolled proliferation, epithelial-mesenchymal transition, invasion, and therapy resistance. Increasing evidence shows that Wnt signaling in tumor cells does not operate in isolation but is dynamically shaped by reciprocal interactions with the tumor microenvironment (TME), including fibroblasts, immune and endothelial cells, extracellular matrix, and metabolic stressors. These bidirectional circuits sustain cancer stemness, remodel stromal architecture, and create immunosuppressive and pro-angiogenic conditions that foster tumor growth as well as metastatic dissemination and colonization. In this review, we examine how canonical and non-canonical Wnt pathways intersect with the TME across distinct stages of the metastatic cascade, from local invasion to the establishment of distant niches. We further evaluate therapeutic approaches targeting Wnt signaling and discuss their potential to overcome immune evasion and metastatic progression when combined with immunotherapy or stromal-targeted agents. Finally, we highlight emerging preclinical models, including organoids and tumor-on-a-chip systems, that are advancing our understanding of Wnt-TME crosstalk. Together, these insights position Wnt signaling as a central orchestrator of cancer progression and metastasis and a promising therapeutic target for improving outcomes in advanced cancer.