Dickkopf1 (DKK1) is a quintessential Wnt antagonist and immunomodulator overexpressed in multiple cancers, including pancreatic, lung, and head and neck. Here, we identify Toll-like receptor 4 (TLR4) as a novel receptor for DKK1 that primes the NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome in macrophages. DKK1 utilizes TLR4 to initiate a MyD88-TAK1-NFkappaB signaling cascade, upregulating NLRP3, HIF1alpha, and pro-interleukin-1beta (pro-IL-1beta). Notably, DKK1-mediated TLR4 activation is differential from Lipopolysaccharide (LPS); while the interaction between MyD88 and IRAK4 is maintained, DKK1 does not induce IRAK4 phosphorylation, IRF3 phosphorylation, or interferon-beta (IFNbeta) expression. DKK1 acts as a priming signal that, upon a second activation signal such as nigericin, induces canonical NLRP3 assembly, Caspase-1-dependent release of IL-1beta and IL-18, and Gasdermin D-mediated pyroptosis. This was confirmed in macrophages using Casp-1, Nlrp3, and MyD88 knockouts. Inhibitor studies identified NFkappaB, TAK1, and PyK2 as key mediators. Furthermore, depletion of platelet-derived DKK1 in Pf4-cre-Dkk1 fl/fl mice attenuated tumor growth in an orthotopic MOC2 model. Given that NLRP3 activation drives tumor progression and immunosuppression in DKK1-overexpressing pancreatic, lung, and head and neck cancers, our findings identify the DKK1-TLR4-TAK1 axis as a therapeutic target for modulating the inflammatory tumor microenvironment.