Abstract LB384: Dickkopf1(DKK1) is a novel endogenous priming ligand for NLRP3 inflammasome activation in macrophages to promote cancer
Authors: Wook-Jin Chae, Theingi Aung, Sujeong Song, Hisashi Harada
Journal: Cancer Research (2025)

Abstract Dickkopf1 (DKK1) is a quintessential Wnt antagonist and has gained significant attention recently with its multifaceted role in modulating immune responses. Elevated levels of DKK1 in multiple cancer types such as gastric, breast, and head and neck cancer underscores its significance as a potential biomarker and therapeutic target for cancer immunotherapy. However, the underlying molecular mechanisms of DKK1’s role in inflammatory diseases remain unclear. Here, we demonstrated that DKK1 acts as an endogenous priming ligand for NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome activation by upregulating pro-inflammatory gene expressions in macrophages. We showed that DKK1 activates transcription factors NFκB and HIF1α to induce expression of NLRP3 and pro-IL-1β proteins, contributing to NLRP3 inflammasome activation. DKK1 induces pyroptosis in macrophages by acting as a priming signal, followed by nigericin as a second activation signal. We showed that various activation signals, such as nigericin, monosodium urate crystal, and silicon dioxide, induce cellular stress in DKK1-primed macrophages, which is sensed by NLRP3 and induces NLRP3 inflammasome assembly. Activation of the NLRP3 inflammasome leads to caspase-1-dependent release of IL-1β and IL-18 and Gasdermin D-mediated pyroptosis. DKK1 induced both IL-1β secretion and pyroptosis upon DKK1 and Nigericin treatment in mouse Bone Marrow-derived Macrophages (mBMDM) and human THP-1 macrophages. We showed that DKK1 and Nigericin induced ASC oligomerization, pro-caspase-1, and pro-IL-1β cleavage, resulting in the assembly of NLRP3 inflammasome. Consistent with these results, Casp-1 KO and Nlrp3 KO mBMDMs showed that NLRP3 inflammasome components are utilized for DKK1-induced IL-1β secretion and pyroptosis. Finally, we showed that DKK1 and Nigericin treatment induces cleavage of GasderminD in THP1 macrophages, confirming that DKK1- primed and Nigericin-activated macrophages underwent canonical NLRP3 inflammasome-mediated pyroptosis. We demonstrated that DKK1 utilizes MyD88 to induce IL-1β production and pyroptosis using WT and MyD88 KO THP1 macrophages. Inhibitor studies indicated that NFκB, TAK1, and PyK2 pathways are key to DKK1-mediated IL-1β secretion and pyroptosis, while other pathways, including mTOR, PI3K, JNK, and p38 MAPK, are not involved. We showed that depletion of platelet-derived DKK1 in Pf4-cre-Dkk1 fl/fl mice attenuated tumor growth in the orthotopic mouse MOC2 tumor model, and intratumoral platelets were a source of DKK1. Taken together, our result showed that DKK1 induces a pro-inflammatory signaling cascade via the MyD88-ΤΑΚ1-NFκB pathway acting as a novel endogenous priming ligand for NLRP3 inflammasome activation in macrophages. Our results highlight DKK1’s role in the modulation of inflammation in cancer and provide new insights for therapeutic approaches to regulate inflammasome activation in cancer. Citation Format: Wook-Jin Chae, Theingi Aung, Sujeong Song, Hisashi Harada. Dickkopf1(DKK1) is a novel endogenous priming ligand for NLRP3 inflammasome activation in macrophages to promote cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB384.