▲ Cutaneous cGVHD is accompanied by extensive immune microenvironmental stress plastic

Discovery 1: Hypoxia is not a "result", but an "engine" for the continued development of the disease"

For a long time, it was generally believed that hypoxia was merely a secondary manifestation of tissue inflammation and injury. However, this study found that in cutaneous cGVHD, hypoxia is far more than just a "trace" left by the disease, but an important driving force that maintains the progression of the disease. The research team used spatial transcriptome, single-cell sequencing and patient skin biopsy to systematically characterize the skin cGVHD immune microenvironment. Revealing that hypoxia occurs throughout the entire process of disease development, this discovery changes the traditional understanding that hypoxia is not a passive result after tissue damage, but an active factor driving the continued development of skin cGVHD.

▲cGVHD skin forms local ectopic tertiary lymphoid structures

Discovery 2: Why can’t skin fibrosis stop?

Further research found that what really makes the disease progress is not a single cell, but a positive feedback network that continues to strengthen itself. The research team discovered for the first time that a new TLS-like structure composed of CD4⁺ T cells, macrophages and fibroblasts was formed within skin lesions. Different from the classic Tfh and B cell interaction structure in lung cGVHD, this structure becomes an important tissue basis for maintaining local chronic inflammation.

▲PI3K inhibitor treatment reduces cGVHD

Discovery 3: If you find the "switch", you have a chance to block skin fibrosis

Since hypoxia relies on this feedback network to be maintained, can this cycle be interrupted? The research results give a positive answer. Regardless of inhibiting HIF-1α, applying PI3Kδ inhibitors, or neutralizing IL-13, they can significantly reduce local hypoxia levels, reduce the formation of TLS-like structures, weaken abnormal communication between immune cells and stromal cells, and significantly improve fibrosis and survival outcomes in multiple skin cGVHD mouse models.