Hypoxia-driven T cell–macrophage–stromal cross-talk sustains fibrosis in preclinical models of cutaneous chronic graft-versus-host disease
Qingxiao Song, Yuxi Xu, Xiaoqi Wang, Wei Wang, Yimei Feng, Ziyi Hu, Fengjuan Tian, Shuhua Wang, Shayna Jankowski, Kiranj Chaudagar, Han Yao, Ting Chen, Rui Wang, Qing Xu, Ya Zhou, Xiaodong Xie, Yuxuan He, Qi Wang, Guancui Yang, Shiqin Huang, Yuqing Liu, Shijie Yang, Lei Gao, Edmund K. Waller, Xi ZhangChronic 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.