Spatiotemporal Evolution of Malignant Hepatocyte Clones Unveils Immune Evasion Features and Therapeutic Vulnerabilities in Hepatocellular Carcinoma

ABSTRACT Hepatocellular carcinoma (HCC), a highly lethal disease often developing in the context of chronic liver disease, is marked by high relapse rates and low 5‐year survival. To investigate the multicellular ecosystem and molecular features of hepatocarcinogenesis and progression, a comprehensive analysis integrating single‐cell and spatial transcriptomics was conducted. Significant alterations were observed in various cell types, notably an increase in liver parenchymal and endothelial cells, which play critical roles in tissue repair and angiogenesis. Scissor + cells, predominantly hepatocytes, were identified as potentially evolving into malignant cells with poor prognosis and enhanced immune evasion capabilities. Key genes associated with Scissor + cells exhibited potential as cancer prognostic markers. Additionally, the disruption of cellular communication networks during malignant progression revealed the evolution of hepatocytes into cancerous phenotypes. The enhanced signaling pathways, such as MDK‐SDC4 and COL4A‐SDC, were identified as pivotal in driving the malignant transformation of hepatocytes. This transformative process, wherein Scissor + cells acquire malignant features, highlights novel mechanisms of cancer progression. These findings provide deeper insights into hepatocarcinogenesis and offer potential avenues for targeted and personalized therapeutic strategies.