The WNT signaling pathway is a critical regulator of development and adult tissue homeostasis and becomes dysregulated in many cancer types. Although hyperactivation of WNT signaling is common, the type and frequency of genetic WNT pathway alterations can vary dramatically between different cancers, highlighting possible cancer-specific mechanisms for WNT-driven disease. In this review, we discuss how WNT pathway disruption contributes to tumorigenesis in different organs and how WNT affects the tumor cell and immune microenvironment. Finally, we describe recent and ongoing efforts to target oncogenic WNT signaling as a therapeutic strategy. SIGNIFICANCE: WNT signaling is a fundamental regulator of tissue homeostasis and oncogenic driver in many cancer types. In this review, we highlight recent advances in our understanding of WNT signaling in cancer, particularly the complexities of WNT activation in distinct cancer types, its role in immune evasion, and the challenge of targeting the WNT pathway as a therapeutic strategy.
