A Single-cell Atlas of Juvenile Nasopharyngeal Angiofibroma Reveals VEGF-Driven Angiogenic Remodeling as a Therapeutic Vulnerability

Background: Juvenile nasopharyngeal angiofibroma (JNA) is a rare locally aggressive vascular sinonasal tumor that primarily affects adolescent males. Despite advances in endoscopic surgery and preoperative embolization, JNA can be associated with major operative bleeding risk and clinically meaningful recurrence, while non-surgical treatment options remain limited. Methods: To define the cellular programs underlying JNA vascularity, we performed single-cell RNA sequencing of JNA tumors (n=2), tumor-adjacent mucosa, and control sinonasal tissue. We analyzed cell composition, differential gene expression, pathway enrichment, and cell-cell communication, followed by Drug2cell-based mapping of transcriptional states to candidate therapeutic targets. Results: JNA contained an expanded fibrovascular compartment composed of endothelial cells, fibroblasts, pericytes, vascular smooth muscle cells, and neural crest-like cells. Neural crest-like cells were enriched in JNA but showed relatively limited transcriptional differences from tumor-adjacent tissue. By contrast, endothelial cells demonstrated the strongest disease-associated remodeling, with enrichment of angiogenesis, extracellular matrix organization, hypoxia response, and cell migration pathways. Endothelial cells also showed downregulation of adaptive immune signaling pathways, suggesting reduced immune engagement within the tumor microenvironment. Intercellular communication analyses revealed dense endothelial-stromal signaling across the JNA fibrovascular network. Drug2cell analysis nominated VEGF/VEGFR signaling as a candidate therapeutic vulnerability, with VEGFR-targeting agents predicted to act primarily on vascular and lymphatic endothelial populations. Conclusions: JNA is organized around an angiogenesis-dominant fibrovascular program driven by endothelial-centered signaling. These data support further investigation of VEGF/VEGFR-directed therapy as a potential adjunctive strategy for patients with recurrent, unresectable, or surgically high-risk JNA.