Deng Guofei, Luo Yusheng, Lin Xiaorong, Zhang Yuzhi, Lin Yuqing, Pan Yuxi, Ruan Yueheng, Mo Xiaocong, Fang Shuo
Scientific Research Center, Department of Oncology, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, China.
Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, China.
Int J Mol Sci. 2026 Feb 20;27(4):2017. doi: 10.3390/ijms27042017.
Fibrosis is a hallmark of the tumor microenvironment in many solid cancers, driving tumor progression, immune evasion, and treatment resistance; however, the molecular and cellular mechanisms underlying fibrogenesis-particularly stromal-immune crosstalk across organs-remain incompletely understood, compounded by organ-specific heterogeneity and a lack of reliable immune-related biomarkers. To address this, we performed an integrative single-cell RNA sequencing (scRNA-seq) analysis of fibrotic tissues from four major organs-liver, lung, heart, and kidney-alongside non-fibrotic controls, applying unsupervised clustering, trajectory inference, cell-cell communication modeling, and gene set variation analysis (GSVA) to map the fibro-immune landscape. Our analysis revealed both conserved and organ-specific features: fibroblasts were the dominant extracellular matrix (ECM)-producing cells in liver and lung, whereas endothelial-derived stromal populations prevailed in heart and kidney. Immune profiling uncovered distinct infiltration patterns-macrophages displayed organ-specific polarization states; T cells were enriched for tissue-resident subsets in lung and mucosal-associated invariant T (MAIT) cells in liver; and B cells exhibited marked heterogeneity, including a pathogenic interferon-responsive subset prominent in pulmonary fibrosis. GSVA further identified divergent signaling programs across organs and lineages, including TGF-β/TNF-α in the heart, NOTCH/mTOR in the kidney, glycolysis/ROS in the lung, and KRAS/interferon pathways in the liver. Cell-cell communication analysis highlighted robust crosstalk between macrophages, T/B cells, and stromal cells mediated by collagen, laminin, and CXCL signaling axes. Together, this cross-organ atlas delineates a highly heterogeneous fibro-immune ecosystem in human fibrotic diseases, revealing shared mechanisms alongside organ-specific regulatory networks, with immediate translational implications for precision anti-fibrotic therapy, immunomodulatory drug repurposing, and the development of context-specific biomarkers for clinical stratification and therapeutic monitoring.
