A Distal Super-Enhancer Regulates CD47 Expression and Promotes Macrophage-Mediated Phagocytosis of Ovarian Cancer Cells

CD47 is an innate immune checkpoint that can protect tumor cells from macrophage-mediated clearance, but the regulatory mechanisms underlying its expression in ovarian cancer (OC) remain incompletely understood. Here, we investigated the epigenetic regulation of CD47 expression in OC. Single-cell and spatial transcriptomic analyses indicated preferential CD47 expression in malignant epithelial cells. Integration of publicly available epigenomic datasets revealed a distal regulatory region with enhancer-associated features across ovarian cancer models and HGSOC patient samples. A genome-wide CRISPR–Cas9 screen further implicated PITX2 and EP300 as regulators of CD47 expression. Chromatin immunoprecipitation assay showed PITX2 and EP300 occupancy at candidate enhancer elements within this CD47 regulatory region. Comparative epigenomic analyses suggested that features of this regulatory landscape are also present in fallopian tube epithelial cells and become more prominent in OC. suTogether, these findings support a PITX2-EP300 regulatory axis associated with CD47 expression and provide evidence for its potential contribution to tumor immune evasion.