Scholarlink

Background <p>Hepatocellular carcinoma (HCC) is the most common primary liver carcinoma with high lethality. Both of hepatitis B virus (HBV) and <i>Clonorchis sinensis</i> (<i>C. sinensis</i>) are critical infectious contributors to HCC development. However, the inter-tumor heterogeneity and tumor microenvironment (TME) of HCC patients with different infectious background remain largely unknown.</p> Methods <p>We compiled a cohort of 269 primary HCC patients to assess the clinical impact of <i>C. sinensis</i> and HBV infections on patient prognosis. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomic (ST-seq) analyses were performed on tumor and adjacent normal samples from <i>C. sinensis</i>-associated HCC (CP), and double-infection HCC (DP) patients. Additionally, we integrated publicly available scRNA-seq and ST-seq datasets from HBV-associated (HP) patients. Immunofluorescence, immunohistochemistry and in vitro experiments were conducted to validate inter-tumor heterogeneity among the three HCC subtypes.</p> Results <p><i>C. sinensis</i> infection is significantly associated with poorer prognosis in HCC patients. Multi-omics analyses revealed distinct inter-tumor heterogeneity in epithelial, immune, and stromal compartments across different HCC subtypes. Tumor cells in the DP group exhibited more malignant marker expression, higher copy number variation scores, increased activation of p53 pathway, and worse survival outcomes. Compared with other HCC subtypes, the TME in DP samples was enriched with <i>SPP1</i><sup>+</sup> macrophages, exhausted CD8<sup>+</sup> T cells and <i>COL1A1</i><sup><i>+</i></sup> fibroblasts. In contrast, the CP and HP groups showed higher proportions of M2-like macrophages and <i>ENPP2</i><sup><i>+</i></sup> liver vascular endothelial cells, respectively.</p> Conclusion <p>These findings decipher the cellular signatures and their interactions within the TME, shedding light on the inter-tumoral heterogeneity driven by different infections, and the development of targeted therapies for infectious HCC.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Integrating single cell- and spatial- resolved transcriptomics unravels the inter-tumor heterogeneity and immunosuppressive landscape in HBV- and Clonorchis sinensis-associated hepatocellular carcinoma

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月5日

查看全文
  • Jiayun Chen,
  • Wenmin Lu,
  • Yanni Lou,
  • Jing Liu,
  • Xiwen Liao,
  • Yunmeng Bai,
  • Guangqing Cheng,
  • Guangzhi Zhu,
  • Ji Feng,
  • Junqi Liu,
  • Zhaoji Liu,
  • Liqun Jia,
  • Jing Zhou,
  • Tao Peng,
  • Guo-Dong Lu,
  • Jigang Wang

摘要

Background

Hepatocellular carcinoma (HCC) is the most common primary liver carcinoma with high lethality. Both of hepatitis B virus (HBV) and Clonorchis sinensis (C. sinensis) are critical infectious contributors to HCC development. However, the inter-tumor heterogeneity and tumor microenvironment (TME) of HCC patients with different infectious background remain largely unknown.

Methods

We compiled a cohort of 269 primary HCC patients to assess the clinical impact of C. sinensis and HBV infections on patient prognosis. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomic (ST-seq) analyses were performed on tumor and adjacent normal samples from C. sinensis-associated HCC (CP), and double-infection HCC (DP) patients. Additionally, we integrated publicly available scRNA-seq and ST-seq datasets from HBV-associated (HP) patients. Immunofluorescence, immunohistochemistry and in vitro experiments were conducted to validate inter-tumor heterogeneity among the three HCC subtypes.

Results

C. sinensis infection is significantly associated with poorer prognosis in HCC patients. Multi-omics analyses revealed distinct inter-tumor heterogeneity in epithelial, immune, and stromal compartments across different HCC subtypes. Tumor cells in the DP group exhibited more malignant marker expression, higher copy number variation scores, increased activation of p53 pathway, and worse survival outcomes. Compared with other HCC subtypes, the TME in DP samples was enriched with SPP1+ macrophages, exhausted CD8+ T cells and COL1A1+ fibroblasts. In contrast, the CP and HP groups showed higher proportions of M2-like macrophages and ENPP2+ liver vascular endothelial cells, respectively.

Conclusion

These findings decipher the cellular signatures and their interactions within the TME, shedding light on the inter-tumoral heterogeneity driven by different infections, and the development of targeted therapies for infectious HCC.