Single-cell transcriptomics reveals tumor microenvironment remodeling in hepatocellular carcinoma with varying tumor subclonal complexity

Introduction The complexity of tumor cell subclonal structure has been extensively investigated in hepatocellular carcinoma. However, the role of subclonal complexity in reshaping the tumor microenvironment (TME) remains poorly understood. Methods We integrated single-cell transcriptome sequencing data from four independent HCC cohorts, involving 30 samples, to decode the associations between tumor subclonal complexity and the TME. We proposed a robust metric to accurately quantify the degree of subclonal complexity for each sample based on discrete copy number variations (CNVs) profiles. Results We found that tumor cells in the high-complexity group originated from the cell lineage with FGB overexpression and exhibited high levels of transcription factors associated with poor survival. In contrast, tumor cells in low-complexity patients showed activation of more hallmark signaling pathways, more active cell-cell communications within the TME and a higher immune activation status. Additionally, cytokines signaling activity analysis suggested a link between HMGB1 expressed by a specific endothelial subtype and T cell proliferation. Discussion Our study sheds light on the intricate relationship between the complexity of subclonal structure and the TME, offering novel insights into potential therapeutic targets for HCC.