Liver cancer stem cells drive hepatocellular carcinoma progression and therapeutic resistance

Abstract

Hepatocellular carcinoma (HCC) is a highly prevalent and lethal malignancy worldwide, with persistently high rates of therapeutic resistance and post-treatment recurrence. Liver cancer stem cells (LCSCs), a distinct subpopulation of cancer cells endowed with stem cell-like properties, have been identified as key drivers of HCC initiation, progression, metastasis, drug resistance, and relapse. This review systematically synthesizes current knowledge on the biological characteristics and cellular origins of LCSCs, their central roles in HCC pathogenesis, and the functional properties of key surface markers (including EpCAM, CD133, CD13, CD24, and CD44) and core signaling pathways (Wnt/β-catenin, Hedgehog, TGF-β, and STAT3). We further elaborate on the dynamic bidirectional interactions between LCSCs and the tumor microenvironment, encompassing immune cell regulation and stromal crosstalk. Finally, we critically evaluate emerging targeted therapeutic strategies against LCSCs, including CAR-T cell immunotherapy directed against LCSC-specific antigens, combination regimens of signaling pathway inhibitors with immune checkpoint blockade, metabolic intervention approaches, and tumor microenvironment reprogramming strategies. We highlight the urgent need to establish standardized detection systems for LCSC-specific markers and to promote triple synergistic therapeutic paradigms that integrate targeted therapy, immunomodulation, and conventional chemotherapy, thereby offering novel perspectives for clinical intervention in HCC.