HRD-Driven Reprogramming of Macrophage Function and Spatial Architecture in High-Grade Serous Ovarian Cancer

High-grade serous ovarian cancer (HGSOC) exhibits homologous recombination deficiency (HRD), but its impact on the immune microenvironment remains unclear. Using single-cell RNA sequencing, spatial transcriptomic inference, and survival analyses, we characterized 166,895 macrophages across HRD subtypes: functional BRCA1/2 inactivation (FBI), HRD-Del (deletions), and HRD-Dup (duplications). FBI macrophages showed lipid metabolism enrichment (S100A8, CD36), HRD-Del macrophages upregulated antigen presentation (HLA-DQA1, HLA-DPB1), and HRD-Dup macrophages displayed interferon-stimulated gene expression (ISG15, MX1). Six macrophage subtypes (C1Q, FCN1, MARCO, MKI67, MMP9, S100A9) exhibited distinct spatial distributions and functions. MKI67+ macrophages correlated with improved survival, while C1Q + subsets predicted worse outcomes. HRD-Dup tumors with high macrophage signatures had better survival, suggesting a favorable immune landscape. Our findings reveal HRD-driven macrophage reprogramming as a key determinant of immune microenvironment composition and clinical outcomes, supporting HRD-specific macrophage-targeted therapies for HGSOC.