The complex dynamics between liver cancer stem cells (CSCs) and immune cells within the tumor microenvironment (TME) are central to the progression of liver cancer. These interactions are critical in creating an immunosuppressive setting that significantly impacts the response to immunotherapy . Liver CSCs, responsible for tumor initiation, metastasis , therapeutic resistance, and recurrence, exhibit heterogeneity and are characterized by various surface markers that contribute to their stemness and metastatic potential.
The origins of liver CSCs are multifaceted, with theories suggesting they may arise from liver stem/progenitor cells, mature hepatocytes, or through the reprogramming of non-CSCs. Identified markers such as CD133, CD90, CD44, and EpCAM have provided insights into the diverse characteristics of liver CSCs, which are vital for their maintenance and immune evasion. Signaling pathways, including Wnt/β-catenin, NOTCH, and IL-6/STAT3, are integral to the self-renewal and differentiation of liver CSCs and are associated with therapeutic resistance and poor prognosis in HCC patients.
Targeting these pathways could offer novel therapeutic strategies. The TME of liver CSCs comprises a range of components, including tumor parenchymal cells, stromal cells, immune cells, cytokines, and the extracellular matrix, all of which contribute to the properties of CSCs. Notably, cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), and immune suppressive cyto.