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Consequently, its cellular composition and tumor microenvironment (TME) remain largely undefined. Here, we performed integrated bulk and single\u2010nucleus multi\u2010omic 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\u2010driven 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\u2010specific chromatin accessibility and DNA hypomethylation, particularly at AP\u20101\u2010enriched regulatory elements. Mechanistically,\u00a0in vitro\u00a0studies confirmed that this response depends on cooperative AP\u20101 and HIF1A signaling. Furthermore, histological analysis of patient tissues demonstrated spatial co\u2010localization of GLUT1\u2010expressing TC1 cells with DLL4\u2010positive EC1 cells. These findings elucidate the epigenetic landscape underlying tumor\u2013stromal interactions and establish the ADM\/VEGFA axis as a critical therapeutic target to disrupt epigenetically controlled angiogenesis in SNSCC.<\/jats:p>","DOI":"10.1002\/advs.202510302","type":"journal-article","created":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T14:45:01Z","timestamp":1767797101000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Single\u2010Nucleus Multi\u2010Omics Reveals Hypoxia\u2010Driven Angiogenic Programs and Their Epigenetic Control in Sinonasal Squamous Cell Carcinoma"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-4483-7952","authenticated-orcid":false,"given":"Chaelin","family":"You","sequence":"first","affiliation":[{"name":"Department of Biological Sciences and Biotechnology Chungbuk National University  Cheongju Republic of 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