The Janus Face of sFRP4 in Cancer: From Mechanistic Complexity to Therapeutic Potential

Secreted frizzled-related protein 4 (sFRP4) has traditionally been regarded as a Wnt antagonist with tumor-suppressive properties. However, growing evidence indicates that its role in cancer is far more complex and highly context-dependent. Depending on tumor type, molecular subtype, epigenetic state, and microenvironmental conditions, sFRP4 may exert either inhibitory or tumor-promoting effects. This functional heterogeneity has important implications for understanding cancer biology and for evaluating the clinical relevance of sFRP4. In this review, we summarize current knowledge of the structural features, regulatory mechanisms, and signaling functions of sFRP4, and discuss how these factors shape its diverse roles across malignancies. We further examine its potential significance in diagnosis, prognosis, therapeutic stratification, and systemic metabolic regulation. A clearer understanding of the context-specific behavior of sFRP4 may help refine its value as a biomarker and support the development of more precise and mechanism-informed therapeutic strategies.