Exploring Single-Cell and Multi-Omics Technologies and Their Role in Unravelling Tumor Heterogeneity of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Tumor heterogeneity is a major obstacle to effective treatment and is poorly understood using traditional bulk sequencing methods. This review highlights the transformative role of single-cell and multi-omics technologies in determining the cellular and molecular complexities of HCC. We summarize recent advances in single-cell transcriptomics, epigenomics, multi-omics, and spatial transcriptomics platforms, emphasizing their applications in characterizing tumor subclones, cancer-associated fibroblast-immune interactions, circulating tumor cells, and immune-resistant phenotypes. Spatial approaches have revealed the architecture of cancer stem cell niches and tertiary lymphoid structures, providing unprecedented insights into tumor organization and microenvironmental crosstalk. Although still in their early stages, clinical trials have begun to incorporate these technologies, underscoring their translational potential. Single-cell and spatial omics have reshaped HCC research by enabling high-resolution profiling of tumor ecosystems and driving the discovery of biomarkers, therapeutic targets, and strategies for patient stratification. However, high cost, technical expertise, and limited accessibility, particularly in resource-constrained settings, are major barriers to its widespread adoption. Addressing these challenges is critical for translating these powerful approaches into clinical practice and for advancing precision medicine for the treatment of liver cancer.