Dickkopf-1 (DKK1), a secreted glycoprotein, was first characterized as an antagonist of canonical Wnt/β-catenin signaling. It is now recognized as a multifunctional regulator, acting through canonical Wnt inhibition, non-canonical Wnt branches, and Wnt-independent axes mediated by the receptor Cytoskeleton-Associated Protein 4 (CKAP4). Elevated circulating or tissue DKK1 is associated with poor prognosis across multiple malignancies and has been proposed as a diagnostic and prognostic biomarker, particularly within multi-marker panels. Yet the receptor- and context-dependent mechanisms underlying its dual effects on tumor behavior remain scattered across the literature, without a unifying explanatory framework. This review consolidates current evidence on DKK1 signaling, its diagnostic and prognostic value across cancer types, and its therapeutic targeting. It also proposes an integrative model—organized around receptor engagement, cellular source, and upstream regulatory control—to explain its context-dependent behavior in cancer. We further summarize DKK1-driven immune evasion and its convergence with resistance to checkpoint blockade and review clinical progress with DKK1-targeting agents. By linking mechanistic insight to biomarker performance, this review aims to support future efforts to validate DKK1 as a clinical biomarker and guide biomarker-driven combination therapies.
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Fiorentino et al. (2026) studied this question.
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