KREMEN2 (kringle containing transmembrane protein 2) is a transmembrane receptor that negatively regulates Wnt/β-catenin signaling by cooperating with Dickkopf proteins to promote endocytosis of Wnt receptors LRP5 and LRP6. In normal physiology, KREMEN2 plays critical roles in limb development and bone formation by attenuating Wnt signaling 1. However, emerging evidence reveals that KREMEN2 functions as an oncogenic driver in multiple human cancers. KREMEN2 is significantly upregulated in colorectal cancer, non-small cell lung cancer (NSCLC), and high-grade serous ovarian cancer compared to normal tissues 123. High KREMEN2 expression correlates with poor prognosis, lymph node metastasis, and advanced cancer stage across multiple cancer types 42. Mechanistically, KREMEN2 promotes cancer cell proliferation and metastasis through activation of PI3K/AKT/mTOR and EGFR/JAK2/STAT3 signaling pathways 25. In SMARCB1-deficient and cBAF-deficient cancers, KREMEN2 transcriptional upregulation depends on CBP/p300 acetyltransferase activity, making CBP/p300 dual inhibitors synthetic lethal therapeutic agents by suppressing KREMEN2 expression and inducing apoptosis 67. These findings establish KREMEN2 as a pan-cancer prognostic biomarker and promising immunotherapeutic and epigenetic target.