Hypoxia-driven T cell-macrophage-stromal cross-talk sustains fibrosis in preclinical models of cutaneous chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation, with cutaneous fibrosis representing a debilitating and treatment-resistant manifestation. We identified a hypoxia-driven inflammatory and fibrotic program in cGVHD skin mediated by a hypoxia-inducible factor 1α-phosphatidylinositol 3-kinase-interleukin-13 (HIF-1α-PI3Kδ-IL-13) signaling axis. Spatial transcriptomics, single-cell RNA sequencing, and multiplex immunofluorescence revealed stabilization of HIF-1α in epidermal cells in hypoxic regions. HIF-1α stabilization was accompanied by IL-13 production from PI3Kδ-activated T cells and macrophage-epidermal cross-talk, which together promoted fibrosis and the formation of tertiary lymphoid structure (TLS)-like aggregates. In human epidermal cell lines and induced pluripotent stem cell-derived skin organoids, IL-13 directly induced HIF-1α expression in keratinocytes under normoxic conditions. HIF-1α expression was further amplified in hypoxic conditions, driving profibrotic signaling. Pharmacologic inhibition of HIF-1α, PI3Kδ, or IL-13 reduced tissue hypoxia, disrupted TLS-like aggregates, and ameliorated disease in murine cGVHD models. These findings identify a targetable circuit linking hypoxia, type 2 inflammation, and immune-stromal dysfunction in cGVHD and provide a translational framework for treating fibrotic cGVHD and related immune-mediated fibrosing diseases.