The Dickkopf-1 (DKK1) Dichotomy in Oncology: New Insights on Tumor Progression and Immune Regulation

Dickkopf-1 (DKK1) is a 266-amino-acid secreted glycoprotein originally identified as a high-affinity antagonist of the canonical Wnt/β-catenin signaling pathway and has emerged as a complex regulator in oncology. While historically considered as a tumor suppressor due to its ability to abrogate Wnt-driven proliferation, recent discoveries highlight a paradoxical pro-oncogenic role across various malignancies. The molecular mechanisms by which DKK1 promotes tumor progression, metastasis, and immune evasion are driven by its interaction with cell-surface receptors, specifically LRP5/6 and CKAP4. The DKK1-CKAP4 axis independently activates PI3K/AKT signaling, facilitating epithelial–mesenchymal transition (EMT), chemoresistance, and the formation of osteolytic bone lesions. Furthermore, DKK1 serves as a critical orchestrator of the tumor microenvironment (TME) by driving comprehensive immune reprogramming. It mediates the recruitment of myeloid-derived suppressor cells (MDSCs) and inactivates cytotoxic CD8+ T cells and natural killer (NK) cells, thereby fostering an immunosuppressive tumor microenvironment and resistance to checkpoint inhibitors. Interestingly, cancer-associated fibroblasts (CAFs) are a primary source of DKK1 in the stroma, where they facilitate immune evasion. Clinically, elevated circulating DKK1 levels correlate with advanced disease stages, increased metastatic potential, and poor overall survival in solid and hematological tumors. When used in combination with established biomarkers, serum DKK1 levels demonstrate significant utility for early detection and therapeutic monitoring. Given its intricate impact on malignancy, DKK1 has become a promising therapeutic target, with ongoing clinical trials investigating neutralizing antibodies such as DKN-01 to disrupt its oncogenic and immunosuppressive signaling. Understanding the context-dependent nature of DKK1 signaling remains essential for refining its application as both a biomarker and a component of emerging precision immunotherapy strategies. By prioritizing the literature from the last decade, this review characterizes DKK1 as a key mediator of tumor progression and immune reprogramming, while assessing its clinical potential as a biomarker and therapeutic target.