Department of Liver Surgery and Transplantation, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
HIM-BGI Omics Center, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences (CAS), BGI Research, Hangzhou, Zhejiang, China.
Guangdong Provincial Key Laboratory of Human Disease Genomics, BGI Research, Shenzhen, Guangdong, China.
College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China.
Institute of Neuroscience, State Key Laboratory of Neuroscience, Key Laboratory of Primate Neurobiology, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China.
Department of Analytical Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
University of Chinese Academy of Sciences, Beijing, China.
Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Shanghai, China.
School of Computer Science and Technology, Xidian University, Xi'an, Shaanxi, China.
BGI Research, Qingdao, Shandong, China.
Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China.
Guangdong Provincial Key Laboratory of Genome Read and Write, BGI Research, Shenzhen, Guangdong, China.
The Center for Microbes, Development and Health, Key Laboratory of Molecular Virology & Immunology, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai, China.
Department of Liver Surgery and Transplantation, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China. gaoqiang@fudan.edu.cn.
Department of Analytical Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. zhouhu@simm.ac.cn.
University of Chinese Academy of Sciences, Beijing, China. zhouhu@simm.ac.cn.
Institute of Neuroscience, State Key Laboratory of Neuroscience, Key Laboratory of Primate Neurobiology, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China. ydsun@ion.ac.cn.
HIM-BGI Omics Center, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences (CAS), BGI Research, Hangzhou, Zhejiang, China. wukui@genomics.cn.
Guangdong Provincial Key Laboratory of Human Disease Genomics, BGI Research, Shenzhen, Guangdong, China. wukui@genomics.cn.
Institute of Intelligent Medical Research (IIMR), BGI Genomics, Shenzhen, Guangdong, China. wukui@genomics.cn.
Department of Liver Surgery and Transplantation, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China. fan.jia@zs-hospital.sh.cn.
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.
