Abstract
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.