Presence of onco-fetal neighborhoods in hepatocellular carcinoma is associated with relapse and response to immunotherapy

Zhizhen Li, Rhea Pai, Saurabh Gupta, Jennifer Currenti, Wei Guo, Anna Di Bartolomeo, Hao Feng, Zijie Zhang, Zhizhen Li, Longqi Liu, Abhishek Singh, Yinqi Bai, Bicheng Yang, Archita Mishra, Katharine Yang, Liang Qiao, Michael Wallace, Yujia Yin, Qiang Xia, Jerry Kok Yen ChanJacob George, Pierce Kah-Hoe Chow, Florent Ginhoux, Ankur Sharma

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)


Onco-fetal reprogramming of the tumor ecosystem induces fetal developmental signatures in the tumor microenvironment, leading to immunosuppressive features. Here, we employed single-cell RNA sequencing, spatial transcriptomics and bulk RNA sequencing to delineate specific cell subsets involved in hepatocellular carcinoma (HCC) relapse and response to immunotherapy. We identified POSTN+ extracellular matrix cancer-associated fibroblasts (EM CAFs) as a prominent onco-fetal interacting hub, promoting tumor progression. Cell-cell communication and spatial transcriptomics analysis revealed crosstalk and co-localization of onco-fetal cells, including POSTN+ CAFs, FOLR2+ macrophages and PLVAP+ endothelial cells. Further analyses suggest an association between onco-fetal reprogramming and epithelial-mesenchymal transition (EMT), tumor cell proliferation and recruitment of Treg cells, ultimately influencing early relapse and response to immunotherapy. In summary, our study identifies POSTN+ CAFs as part of the HCC onco-fetal niche and highlights its potential influence in EMT, relapse and immunotherapy response, paving the way for the use of onco-fetal signatures for therapeutic stratification.Ginhoux and colleagues perform multi-omic characterization of hepatocellular carcinoma and identify an onco-fetal niche that includes fibroblasts, macrophages and endothelial cells and influences immunotherapy response and relapse.
Original languageEnglish
Pages (from-to)167-186
Number of pages20
JournalNature Cancer
Issue number1
Early online date2024
Publication statusPublished - Jan 2024


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