ArticleCell discovery2025
Stromal architecture and fibroblast subpopulations with opposing effects on outcomes in hepatocellular carcinoma.
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Article in Cell discovery, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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48citing papers in PubMed
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Who cites it
48 citing papers in PubMed.
- Integrated single-cell multi-omics characterization reveals lipid-associated macrophage-mediated immunosuppression in neoadjuvant immunotherapy of hepatocellular carcinoma.Nature communications · 2026Trial
- Assessment of liver fibrosis and tumor burden in hepatocellular carcinoma using [European journal of nuclear medicine and molecular imaging · 2026Trial
- Cancer-associated fibroblasts in therapeutic resistance of hepatocellular carcinoma: evidence, mechanisms, and translational implications.Medical oncology (Northwood, London, England) · 2026Review
- Unraveling the tapestry: Lessons from multi-omics and spatial biology in hepatocellular cancer.Hepatology (Baltimore, Md.) · 2026Review
- Multi-omics-driven precision medicine.iMeta · 2026Review
- Review
- Spatial ecotype in tumor immune exclusion: from spatial architecture to therapeutic strategies.Molecular cancer · 2026Review
- β-glucan elicits APOE-dependent peripheral trained immunity to suppress hepatocellular carcinoma.Journal for immunotherapy of cancer · 2026Article
- Glypican-3-targeted therapy in hepatocellular carcinoma: biological insights and therapeutic strategies.Cancer gene therapy · 2026Review
- The value ofEuropean journal of nuclear medicine and molecular imaging · 2026Article
- Unraveling the roles of fibroblast activation protein‑positive cancer‑associated fibroblasts in cancer: From mechanisms to therapy (Review).International journal of oncology · 2026Review
- Molecular phenotypes and spatial archetypes: A new framework for cancer-associated fibroblasts.Cancer cell · 2026Review
- Spatiotemporal voxel-wise concordance betweenEuropean journal of nuclear medicine and molecular imaging · 2026Article
- POSTN(+) fibroblasts and SPP1(+) macrophages in scar formation: A review of mechanisms and therapeutic targets (Review).Molecular medicine reports · 2026Review
- Targeting tumor dormancy: the next frontier in gastrointestinal stromal tumor therapy.Neoplasia (New York, N.Y.) · 2026Review
- Spatial remodeling of the tumor immune microenvironment in hepatocellular carcinoma with cirrhosis driven by Treg-CD8⁺T cell crosstalk via the SPP1-ITGA4 axis.Translational oncology · 2026Article
- The predictive value ofEuropean journal of nuclear medicine and molecular imaging · 2026Article
- Spatial transcriptomic-metabolic features of tumor foci and tumor capsule in microvascular invasion with hepatocellular carcinoma: A spatial multi-omics study.PLoS medicine · 2026Article
- Review
- Decoding the CAF-TAM axis: multi-omics dissection and therapeutic targeting of stromal-immune crosstalk in the tumor microenvironment.Cell death & disease · 2026Review
Corrections and comments
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Authors and funding
37 authors.
Yifei Cheng *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.
Xiaofang Chen *HIM-BGI Omics Center, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences (CAS), BGI Research, Hangzhou, Zhejiang, China.
Li Feng *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.
Zhicheng Yang *Department of Analytical Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.ORCID http://orcid.org/0000-0001-7477-2984
Liyun Xiao *HIM-BGI Omics Center, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences (CAS), BGI Research, Hangzhou, Zhejiang, China.
Bin XiangKey Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Shanghai, China.
Xiaodong WangSchool of Computer Science and Technology, Xidian University, Xi'an, Shaanxi, China.ORCID http://orcid.org/0000-0003-1711-2933
Dongbin LiuHIM-BGI Omics Center, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences (CAS), BGI Research, Hangzhou, Zhejiang, China.ORCID http://orcid.org/0000-0003-2870-5187
Penghui LinHIM-BGI Omics Center, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences (CAS), BGI Research, Hangzhou, Zhejiang, China.
Jieyi ShiDepartment 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.
Guohe SongDepartment 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.ORCID http://orcid.org/0000-0002-9947-7268
Wulei QianSchool of Computer Science and Technology, Xidian University, Xi'an, Shaanxi, China.
Boan ZhangSchool of Computer Science and Technology, Xidian University, Xi'an, Shaanxi, China.
Yanan XuDepartment 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.ORCID http://orcid.org/0000-0002-8843-9426
Zheng GaoDepartment 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.
Lv ChenDepartment 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.
Yingcheng WuDepartment 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.
Jiaqiang MaDepartment 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.
Youpei LinDepartment 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.
Haichao ZhaoDepartment 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.
Lihua PengHIM-BGI Omics Center, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences (CAS), BGI Research, Hangzhou, Zhejiang, China.
Xuebin MaoBGI Research, Qingdao, Shandong, China.
Yang LiuHIM-BGI Omics Center, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences (CAS), BGI Research, Hangzhou, Zhejiang, China.
Hao HouHIM-BGI Omics Center, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences (CAS), BGI Research, Hangzhou, Zhejiang, China.
Mingyu YangHIM-BGI Omics Center, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences (CAS), BGI Research, Hangzhou, Zhejiang, China.
Yuan JiDepartment of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China.
Xiaoying WangDepartment 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.
Jian ZhouDepartment 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.ORCID http://orcid.org/0000-0002-2118-1117
Xun XuGuangdong Provincial Key Laboratory of Genome Read and Write, BGI Research, Shenzhen, Guangdong, China.ORCID http://orcid.org/0000-0002-5338-5173
Xiyang LiuSchool of Computer Science and Technology, Xidian University, Xi'an, Shaanxi, China.
Wu WeiKey Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Shanghai, China.ORCID http://orcid.org/0000-0001-5643-8739
Xiaoming ZhangThe Center for Microbes, Development and Health, Key Laboratory of Molecular Virology & Immunology, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai, China.ORCID http://orcid.org/0000-0001-6732-9132
Qiang GaoDepartment 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.ORCID http://orcid.org/0000-0002-6695-9906
Hu ZhouDepartment of Analytical Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. zhouhu@simm.ac.cn.ORCID http://orcid.org/0000-0001-7006-4737
Yidi SunInstitute 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.ORCID http://orcid.org/0000-0002-4191-2917
Kui WuHIM-BGI Omics Center, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences (CAS), BGI Research, Hangzhou, Zhejiang, China. wukui@genomics.cn.ORCID http://orcid.org/0000-0002-6857-7231
Jia FanDepartment 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.ORCID http://orcid.org/0000-0001-5158-629X
Funding
Ministry of Science and Technology of the People's Republic of China (Chinese Ministry of Science and Technology) 2020YFA0509000Ministry of Science and Technology of the People's Republic of China (Chinese Ministry of Science and Technology) 2022YFA1302902National Natural Science Foundation of China (National Science Foundation of China) 32370978National Natural Science Foundation of China (National Science Foundation of China) 81961128025National Natural Science Foundation of China (National Science Foundation of China) 82090053National Natural Science Foundation of China (National Science Foundation of China) 82103037National Natural Science Foundation of China (National Science Foundation of China) 82130077National Natural Science Foundation of China (National Science Foundation of China) 82172860National Natural Science Foundation of China (National Science Foundation of China) 82203643National Natural Science Foundation of China (National Science Foundation of China) 82394450National Natural Science Foundation of China (National Science Foundation of China) U23A6010Science and Technology Commission of Shanghai Municipality (Shanghai Municipal Science and Technology Commission) 19XD1420700Science and Technology Commission of Shanghai Municipality (Shanghai Municipal Science and Technology Commission) 2018SHZDZX05Science and Technology Commission of Shanghai Municipality (Shanghai Municipal Science and Technology Commission) 20XD1424900Science and Technology Commission of Shanghai Municipality (Shanghai Municipal Science and Technology Commission) 22YF1407200
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.
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