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Background Endometrial Cancer (EC) is the most common gynecologic malignancy in the United States and remains among the tumor types with limited improvement in overall survival over the past decade. The most recent molecular classification, based on The Cancer Genome Atlas (TCGA) stratifies EC into four distinct groups: POLE-mutated, mismatch repair-deficient/microsatellite instability-high (MMRd/MSI-H), no specific molecular profile (NSMP), and p53-abnormal (p53abn). 1 These subtypes are prognostically informative, including response to immune checkpoint inhibitors (ICI), recurrence risk, and overall survival. Each subgroup has a biologically distinct makeup (tumor biology, immune cell infiltration).2 3 MMRd tumors account for approximatively 25-30% of EC patients and have intermediate immune infiltration. Despite these tumors having good responses to ICI (>50%), around 40% of patients will recur. The mechanisms driving immune cell infiltration, immunosuppressive reprogramming, and immune evasion in MMRd EC, remain poorly understood. DKK1, a secreted inhibitor of the canonical WNT signaling pathway via binding to LRP5/6 co-receptors, is emerging as a potential key regulator of immunosuppressive reprogramming.4–6 High DKK1 levels have been associated with expansion of myeloid-derived suppressor cells (MDSCs) and impaired cytotoxic activity of CD8+ T cells and natural killer (NK) cells in several solid tumors. In EC, analysis of the TCGA-UCEC datasets has shown global upregulation of DKK1.4 7 A recent study in breast cancer identified stromal fibroblasts as major contributors to extracellular DKK1, leading to suppression of NK cell cytotoxicity.8 Methods We analyzed 104 FFPE tumor samples from newly diagnosed, ICI-naïve EC patients with MMRd tumors who underwent surgical staging at The Ohio State University. The cohort included 14 low-grade and 90 high-grade MMRd tumors. Total RNA was extracted and analyzed using Nanostring IO gene expression panel. Differential gene expression, immune deconvolution, and immunofluorescence were performed to characterize the tumor immune microenvironment.Results High-grade MMRd tumors showed significant upregulation of genes associated with tumor proliferation, invasion, WNT signaling, and stromal fibroblasts activity. Notably, DKK1 expression was 2.3-fold higher in the tumor microenvironment (TME) of high-grade versus low-grade MMRd tumors. Similarly, LAG3, a marker for CD8+ T and NK cell exhaustion, resulted 2.61-fold higher. Deconvolution and immunofluorescence analysis revealed a significant reduction of activated NK, monocytes, neutrophils, B and dendritic cells, along with the upregulation of regulatory T lymphocytes.Conclusions These results highlight the potential of targeting DKK1 in combination with ICI therapies, to enhance NK cells activation in MMRd tumors and improve immunotherapeutic outcomes.References Levine DA, et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67–73.Dai Y, et al. Tumor immune microenvironment in endometrial cancer of different molecular subtypes: evidence from a retrospective observational study. Front Immunol. 2022;13:1035616.Talhouk A, et al. Molecular subtype not immune response drives outcomes in endometrial carcinoma. Clin Cancer Res. 2019;25(8):2537–2548.Chu HY, et al. Dickkopf-1: a promising target for cancer immunotherapy. Front Immunol. 2021;12:658097.Qian J, et al. Development of therapeutic monoclonal antibodies against DKK1 peptide-HLA-A2 complex to treat human cancers. J Immunother Cancer. 2024;12(1).Rinella, L, et al. Dickkopf-1 (DKK1) drives growth and metastases in castration-resistant prostate cancer. Cancer Gene Ther. 2024;31(8):1266–1279.Arend R, et al. DKK1 is a predictive biomarker for response to DKN-01: results of a phase 2 basket study in women with recurrent endometrial carcinoma. Gynecol Oncol. 2023;172:82–91.Lee S, et al. Stroma-derived Dickkopf-1 contributes to the suppression of NK cell cytotoxicity in breast cancer. Nat Commun. 2025;16(1):1183.Ethics Approval This study was approved by the Institutional Review Board at The Ohio State University (IRB Nos. 2021C0163, 2021C0145). Given the retrospective nature of the study and utilization of archival patient tissue, a waiver a consent was granted by the institutional ethics committee.