Cancer stem cells in hepatocellular carcinoma: therapy resistance and emerging treatments

Hepatocellular carcinoma (HCC) imposes a significant global cancer mortality burden, with conventional therapies (surgery, ablation, chemotherapy, radiotherapy) and newer modalities (targeted agents, immune checkpoint inhibitors) limited by therapeutic resistance. Notably, liver cancer stem cells (Liver-CSCs)-defined by their self-renewal and unlimited proliferative capacity-drive tumor initiation, metastasis, heterogeneity, and therapy resistance. This review synthesizes current knowledge on Liver-CSCs, focusing on their distinctive features, supporting microenvironments, signaling pathways, and therapy resistance mechanisms. We also examine novel therapeutic strategies targeting these cells. Clinically, we evaluate recent research, identify knowledge gaps, and suggest potential directions for advancing HCC therapies. Finally, we discuss how these insights may inform development of more effective treatments to improve clinical HCC management. Understanding Liver-CSC biology and treatment resistance mechanisms will enable better-tailored therapies to overcome these challenges and enhance patient outcomes.