A Hypoxia Associated STC2 High Endothelial Subpopulation is Linked to Lipid Metabolic Reprogramming, Pathological Angiogenesis, and Immune Remodeling in Head and Neck Squamous Cell Carcinoma.

Purpose: Hypoxia drives malignant advancement and immune escape in HNSCC, but its cell‑type‑specific regulatory circuitry within the TME remains insufficiently elucidated. This study systematically characterizes hypoxia‑associated molecular programs and identifies core genes with relevance to prognosis and therapeutic response. Methods: Bulk, single‑cell, and spatial transcriptomic datasets from independent patient cohorts were integrated. Hypoxia‑associated gene signatures and two molecular subtypes were constructed through unsupervised clustering. A consensus of eight machine‑learning algorithms identified STC2 as the key hypoxia mediator. Bioinformatics analyses encompassing enrichment, CellChat, scMetabolism, and scTenifoldKnk were conducted. STC2 expression was confirmed by RT‑qPCR, immunohistochemistry, and multiplex immunofluorescence. Functional experiments using STC2‑silenced HUVECs included scratch wound‑healing, CCK‑8, and immunofluorescence staining to assess endothelial migration, viability, and cytoskeletal organization. Candidate drugs were explored through pharmacogenomic databases, molecular docking, and molecular dynamics simulations. Results: The hypoxia‑derived signature predicted reduced survival, enhanced angiogenesis, and an immunosuppressive TME. STC2 was predominantly enriched in a distinct endothelial subpopulation marked by active hypoxia‑driven fatty acid metabolism and ANGPT2‑expressing angiogenic signaling. In silico knockout of STC2 weakened hypoxia‑induced angiogenic and immune‑related pathways. CellChat analysis revealed altered GALECTIN‑ and ANGPTL‑mediated communication between this endothelial subset and immune populations. High STC2 levels were associated with immunotherapy resistance and with increased sensitivity to four candidate compounds. PLX4032 and Midostaurin demonstrated stable binding interactions with STC2 in computational analyses. Conclusion: STC2 is preferentially expressed in a hypoxia‑associated endothelial subpopulation characterized by lipid metabolic activity, angiogenic features, and immune‑regulatory crosstalk. Functional assays support a role for STC2 in endothelial viability, migration, and angiogenic function, while its involvement in lipid metabolism and immune modulation requires further investigation. These findings highlight the potential value of STC2 for patient stratification and as a target for future therapeutic exploration in HNSCC.