Single-cell profiles delineate immune cell remodeling and enhanced tumor-fibroblast interaction of hepatoblastoma after chemotherapy
- Cell Rep Med. 2025 Oct 21;6(10):102401. doi: 10.1016/j.xcrm.2025.102401.
- 1. Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai 201102, China; Shanghai Key Laboratory of Birth Defect, Children's Hospital of Fudan University, Shanghai 201102, China.
- 2. Department of Pathology, Children's Hospital of Fudan University, Shanghai 201102, China.
- 3. Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai 201102, China; Shanghai Key Laboratory of Birth Defect, Children's Hospital of Fudan University, Shanghai 201102, China. Electronic address: [email protected].
- 4. Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai 201102, China; Shanghai Key Laboratory of Birth Defect, Children's Hospital of Fudan University, Shanghai 201102, China. Electronic address: [email protected].
- 5. Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai 201102, China; Shanghai Key Laboratory of Birth Defect, Children's Hospital of Fudan University, Shanghai 201102, China. Electronic address: [email protected].
Hepatoblastoma (HB), the most common pediatric liver Cancer, is typically treated with chemotherapy, yet its impact on the tumor microenvironment (TME) and mechanisms of chemoresistance remain unclear. We perform single-cell RNA Sequencing (scRNA-seq) on 32 HB tumors pre- and post-chemotherapy, integrating data from spatial transcriptomics, bulk transcriptomics, multiplexed immunofluorescence, and patient-derived xenografts. Chemotherapy enriches CD69+CD8+ T cells and shifted myeloid cells toward immune-activating phenotypes. HB tumor cells exhibit both hepatic and mesenchymal features, with hepatic-like cells showing greater chemoresistance. A subset of AFP-high hepatic tumor cells expresses high Fibroblast Growth Factor receptor 4 (FGFR4) and showed elevated proliferation. Post-treatment, mesenchymal-like tumor cells and MMP11+ cancer-associated fibroblasts enhance FGF-FGFR signaling. FGFR4 inhibition significantly suppressed tumor growth in xenografts. These findings provide a high-resolution landscape of the HB immune TME and highlight cancer-fibroblast interactions, especially via FGF signaling, as key contributors to chemoresistance.