FAP+ fibroblasts orchestrate tumor microenvironment remodeling in renal cell carcinoma with tumor thrombus

作者：Jiacheng Ma, Yan Huang, Jie Chen, Yang Li, Rongyan Yao, Xiubin Li, Qiyang Liang, Xinran Chen, Cheng Peng, Kan Liu, Yuanjun Zhai, Xu Zhang, Xin Ma, Xiaowen Wang, Qingbo Huang, Fuchu He · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-64447-2 · 被引用次数：6 · 研究领域：Extracellular vesicles in disease、Renal cell carcinoma treatment、Peptidase Inhibition and Analysis

Tumor thrombus (TT) worsens prognosis and complicates surgery in renal cell carcinoma (RCC), yet its formation mechanisms remain unclear. Here, we perform integrative single-cell and spatial transcriptomic analyses on 71 tissues and 48 sections from RCC patients with or without TT. The cellular and spatial atlas reveals distinct TT-associated tumor microenvironment remodeling characterized by the enrichment of FAP+ fibroblasts. These FAP+ fibroblasts are spatially contiguous to aggressive cancer cells and promote their malignant phenotypes in vitro. Their abundance inversely correlates with functional NK cells, suggesting roles in tumor invasion and immune evasion. Furthermore, single-cell multiomics analysis identifies tumor pericytes as a source of FAP+ fibroblasts and delineates transcription factor dynamics underlying pericyte-fibroblast transition. Finally, high levels of FAP+ fibroblasts are associated with poor prognosis and predict a weaker response to anti-VEGF-based therapy. In conclusion, our study highlights FAP+ fibroblasts as drivers of aggressive RCC with TT, suggesting potential therapeutic targets. Tumour thrombus (TT) complicates renal cell carcinoma (RCC) treatment. Here, authors conduct an integrative single-cell RNA sequencing and spatial transcriptomic analyses on RCC patients with and without TT and identify FAP+ fibroblasts as drivers for TT formation.