Spatial Single-Cell Atlas Reveals KSHV-Driven Broad Cellular Reprogramming, Progenitor Expansion, Immune and Vascular Remodeling in Kaposi's Sarcoma

Kaposis sarcoma (KS) is a highly inflammatory, angiogenic tumor driven by Kaposis sarcoma-associated herpesvirus (KSHV), yet the origins of tumor cells and mechanisms of progression remain unclear. Here, we present the first spatial single-cell atlas of KS, profiling 256 samples across patch, plaque, and nodular lesions and normal controls. We identify CD34 progenitor lymphatic endothelial cells (LECs) as the primary targets of KSHV, whose clonal expansion drives tumor growth. KSHV infection induces widespread cellular reprogramming across the tumor microenvironment, including LECs, vascular endothelial cells, fibroblasts, and macrophages, generating hybrid phenotypes that support angiogenesis, inflammation, and immune modulation. KSHV macrophages are enriched in tumor-proximal niches, further promoting a proangiogenic, immunosuppressive environment. Spatial analysis reveals evolving tumor-associated niches, with a core-to-periphery gradient correlating with infection, immune modulation, and cellular remodeling. We identify disease progression predictive signatures, offering mechanistic insights into KS pathogenesis and potential new therapeutic strategies by reprogramming the tumor microenvironment. Highlights CD34+ progenitor lymphatic endothelial cells are the primary KSHV target cells, with their clonal expansion driving Kaposis sarcoma growth. KSHV infection reprograms broad cell types into hybrid identities, and drives tumor-specific niche and vascular remodeling, endothelial plasticity, and immune modulation. KSHV-reprogrammed macrophages drive inflammation, angiogenesis, and immune modulation. Spatially resolved molecular and cellular signatures predict Kaposis sarcoma progression, offering novel therapeutic strategies targeting the tumor microenvironment.