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We generated an integrated multiomic dataset of early-stage, treatment-naive diffuse cutaneous SSc skin. Skin biopsies were analyzed by single-nuclei multiome sequencing (snRNA-Seq and snATAC-Seq) and two spatial transcriptomic methods to comprehensively determine molecular changes. We identified an immunomodulatory niche within the papillary, hypodermis, and vascular regions enriched for activated myeloid cells and fibroblasts characterized by expression of genes such as\n                    <jats:italic>CXCL12<\/jats:italic>\n                    ,\n                    <jats:italic>APOE<\/jats:italic>\n                    , and\n                    <jats:italic>C7<\/jats:italic>\n                    . Pathway analyses showed significant enrichment of PI3K\/AKT\/mTOR signaling pathway expression in these cellular niches, driven by profibrotic growth factor signaling networks. Macrophage subclustering showed SSc-specific macrophage activation of IL-6\/JAK\/STAT signaling and enrichment of oxidative phosphorylation pathways. Ligand-receptor analysis revealed that SSc macrophages secrete PDGF and TGF-\u03b2 to activate SSc-dominant fibroblast subclusters. Spatial transcriptomic analyses showed monocyte-derived MRC1\n                    <jats:sup>+<\/jats:sup>\n                    macrophages express PDGF near\n                    <jats:italic>\n                      PDGFR\n                      <jats:sup>hi<\/jats:sup>\n                      THY1\n                      <jats:sup>hi<\/jats:sup>\n                    <\/jats:italic>\n                    fibroblasts. Multiomic data integration and spatial transcriptomic neighborhood analysis revealed the colocalization of fibroblasts, macrophages, and T cells around the vasculature. These data suggest that interactions between activated immune cells and immunomodulatory fibroblasts around vascular niches are an early event in scleroderma pathogenesis.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.198954","type":"journal-article","created":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T17:01:09Z","timestamp":1766077269000},"source":"Crossref","is-referenced-by-count":10,"title":["Multimodal analyses of early, untreated systemic sclerosis skin identify a proinflammatory vascular niche of macrophage-fibroblast signaling"],"prefix":"10.1172","volume":"11","author":[{"given":"Helen C.","family":"Jarnagin","sequence":"first","affiliation":[{"name":"Department of Biomedical Data Science, and"},{"name":"Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, 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