Single‐Nucleus Multi‐Omics Reveals Hypoxia‐Driven Angiogenic Programs and Their Epigenetic Control in Sinonasal Squamous Cell Carcinoma

ABSTRACT Sinonasal squamous cell carcinoma (SNSCC) is a rare malignancy with poorly understood molecular drivers. Consequently, its cellular composition and tumor microenvironment (TME) remain largely undefined. Here, we performed integrated bulk and single‐nucleus multi‐omic analyses to map the SNSCC ecosystem. Within the malignant compartment, we identified five distinct populations, with hypoxic (TC1) and proliferative (TC2) subtypes associated with adverse clinical outcomes. Functionally, TC1 cells orchestrate a hypoxia‐driven angiogenic program via coordinated secretion of adrenomedullin (ADM), MIF, and VEGFA, promoting endothelial tip cell (EC1) differentiation. Integrative analysis revealed these transcriptional programs are underpinned by tumor‐specific chromatin accessibility and DNA hypomethylation, particularly at AP‐1‐enriched regulatory elements. Mechanistically, in vitro studies confirmed that this response depends on cooperative AP‐1 and HIF1A signaling. Furthermore, histological analysis of patient tissues demonstrated spatial co‐localization of GLUT1‐expressing TC1 cells with DLL4‐positive EC1 cells. These findings elucidate the epigenetic landscape underlying tumor–stromal interactions and establish the ADM/VEGFA axis as a critical therapeutic target to disrupt epigenetically controlled angiogenesis in SNSCC.