A Single-Cell Atlas of Uterine Carcinosarcoma from Diverse Ancestries

Uterine carcinosarcoma (UCS) is an aggressive endometrial malignancy characterized by epithelial-mesenchymal plasticity, early metastasis, and poor therapeutic response. However, its single-cell organization and microenvironmental interactions remain incompletely defined, particularly in patients of African ancestry who are underrepresented in genomic datasets despite a disproportionate disease burden. Here, we generate a single-cell transcriptomic atlas of UCS from a diverse cohort enriched for patients of African ancestry, integrated with whole-genome sequencing. We identify pronounced inter-patient heterogeneity and resolve epithelial-like, mesenchymal-like, transitional, and stem-like malignant states. Copy-number and trajectory analyses reveal multiple subclones linked along epithelial, progenitor-like, and mesenchymal programs, consistent with metaplastic transitions. Compared to normal endometrium, primary tumors exhibit epithelial-mesenchymal-transition (EMT), mTORC1, and glycolytic programs, whereas metastases show enhanced TNFα-NFκB signaling linked to invasion. The tumor microenvironment comprises diverse immunosuppressive myeloid states and heterogeneous cancer-associated fibroblast populations, including pericyte-like and matrix-remodeling subsets that act as communication hubs via chemokine and immune-checkpoint signaling. These data define the UCS cellular ecosystem in which malignant plasticity is coupled to stromal-immune cell remodeling in a patient cohort of diverse ancestries.