Topic: Cancer Stem Cells, Tumor Plasticity, and Tumor Heterogeneity in Hepatocellular Carcinoma

Cancer stem cells—a subpopulation of cells endowed with self-renewal capacity and multidirectional differentiation potential—are now recognized as principal drivers of tumor initiation, metastasis, and therapy resistance in HCC. Importantly, the behavior and maintenance of CSCs are not autonomous but critically dependent on complex bidirectional crosstalk with the tumor microenvironment (TME). Tumor plasticity has emerged as a recognized hallmark of cancer, enabling cancer cells to undergo molecular and phenotypic changes that allow them to adopt different differentiation states. In HCC, tumors are known to contain more stemness or less differentiated cell states that are resistant to therapy and associated with tumor relapses. Tumor heterogeneity in HCC operates at multiple levels—intertumoral, intratumoral, spatial, and temporal. This heterogeneity evolves over time as CSCs undergo (epi)genetic alterations or encounter microenvironmental changes, enabling them to exhibit plasticity and differentiate into various resistant tumor cell types. The multidimensional nature of HCC heterogeneity poses formidable challenges for biomarker development, patient stratification, and therapeutic decision-making. Recent technological breakthroughs—including single-cell RNA sequencing, spatial transcriptomics, barcoded CRISPR-Cas9 screening, and patient-derived organoid models—have opened new windows into this complexity, enabling researchers to dissect CSC heterogeneity, map cellular state transitions, and identify novel therapeutic vulnerabilities.

The convergence of these three themes—CSCs, plasticity, and heterogeneity—defines the contemporary frontier of HCC research. Understanding how CSCs maintain their stemness, how they adapt and evolve under therapeutic pressure, and how their interactions with the tumor microenvironment shape disease progression and treatment response is essential for developing more effective therapies. This Special Issue aims to bring together cutting-edge research that explores the molecular mechanisms governing CSC maintenance and plasticity, the role of the tumor microenvironment in shaping CSC behavior, the application of single-cell and spatial omics technologies to map heterogeneity, and the development of novel therapeutic strategies designed to overcome CSC-driven therapy resistance. We welcome original research articles, reviews, mini-reviews, clinical trials, case reports, commentaries, methodological studies, and perspectives focused on, but not limited to, the following topics:

● Molecular mechanisms of liver cancer stem cell self-renewal and maintenance;

● Tumor cell-state plasticity and developmental heterogeneity in HCC;

● Metabolic reprogramming of liver cancer stem cells;

● CSC–immune microenvironment crosstalk;

● Single-cell and spatial multi-omics dissection of HCC heterogeneity;

● Clonal evolution, lineage tracing in HCC;

● Patient-derived organoid models for studying CSC heterogeneity and drug response;

● Viral and etiological drivers of LCSC reprogramming;

● Novel therapeutic strategies targeting CSCs and tumor plasticity;

● Biomarkers of CSC-driven heterogeneity for patient stratification and precision medicine.