Stromal architecture and fibroblast subpopulations with opposing effects on outcomes in hepatocellular carcinoma
Yifei Cheng, Xiaofang Chen, Feng Li, Zhicheng Yang, Liyun Xiao, Bin Xiang, Xiaodong Wang, Dongbing Liu, Penghui Lin, Jie-Yi Shi, Guohe Song, Wulei Qian, Boan Zhang, Yanan Xu, Zheng Gao, Lv Chen, Yingcheng Wu, Jiaqiang Ma, Youpei Lin, Haichao Zhao, Li‐Hua Peng, Xuebin Mao, Yang Liu, Hao Hou, Ming‐Yu Yang, Yuan Ji, Xiaoying Wang, Jian Zhou, Xun Xu, Xi-Yang Liu, Wei Wu, Xiaoming Zhang, Qiang Gao, Hu Zhou, Yidi Sun, Kui Wu, Jia Fan
Abstract
Dissecting the spatial heterogeneity of cancer-associated fibroblasts (CAFs) is vital for understanding tumor biology and therapeutic design. By combining pathological image analysis with spatial proteomics, we revealed two stromal archetypes in hepatocellular carcinoma (HCC) with different biological functions and extracellular matrix compositions. Using paired single-cell RNA and epigenomic sequencing with Stereo-seq, we revealed two fibroblast subsets CAF-FAP and CAF-C7, whose spatial enrichment strongly correlated with the two stromal archetypes and opposing patient prognosis. We discovered two functional units, one is the intratumor inflammatory hub featured by CAF-FAP plus CD8_PDCD1 proximity and the other is the marginal wound-healing hub with CAF-C7 plus Macrophage_SPP1 co-localization. Inhibiting CAF-FAP combined with anti-PD-1 in orthotopic HCC models led to improved tumor regression than either monotherapy. Collectively, our findings suggest stroma-targeted strategies for HCC based on defined stromal archetypes, raising the concept that CAFs change their transcriptional program and intercellular crosstalk according to the spatial context.