Stemness plasticity in hepatocellular carcinoma: spatial niches and therapeutic implications

Abstract

Hepatocellular carcinoma (HCC) remains a major global health burden, with therapeutic resistance limiting the long-term efficacy of current treatments. Although cancer stem cell (CSC) models have been proposed to explain tumor initiation and relapse, strategies targeting marker-defined CSC populations have shown limited clinical benefit. Increasing evidence indicates that stemness in HCC is not a fixed cellular trait but a dynamic and reversible state that can be induced, maintained, and re-established under therapeutic pressure. This stemness plasticity is regulated by tumor-intrinsic signaling pathways, including transforming growth factor beta, Yes-associated protein/transcriptional coactivator with PDZ-binding motif, and Wnt/β-catenin, and stabilized by epigenetic and post-transcriptional mechanisms such as N6-methyladenosine modification. In parallel, spatially organized tumor microenvironmental niches composed of cancer-associated fibroblasts, macrophages, and endothelial cells provide critical signals that support stem-like phenotypes and immune evasion. These interconnected mechanisms collectively contribute to therapeutic resistance and tumor progression. This review synthesizes current evidence linking stemness plasticity to spatial niche regulation and treatment failure in HCC, and outlines a therapeutic framework that integrates targeting of intracellular regulatory programs with disruption of microenvironmental support systems. We further discuss the implications of this framework for the development of combination strategies and dynamic biomarkers that better capture the context-dependent nature of stemness. Together, these insights support a shift from targeting static cell populations toward targeting the regulatory processes that govern tumor cell plasticity in HCC.