The Emerging Role of Tumor Microenvironmental Stimuli in Regulating Metabolic Rewiring of Liver Cancer Stem Cells

SIMPLE SUMMARY: Increasing evidence indicates that cancer stem cells (CSCs) are the main factor responsible for therapeutic resistance and tumor relapse in primary liver cancer (PLC). This could also be related to the peculiar metabolic phenotype of liver CSCs. Although metabolic reprogramming is currently considered a hallmark of cancer, including PLC, no consensus has been reached with respect to the metabolic features of liver CSCs, which may shift between different metabolic states. CSC plasticity can be controlled not only by several cell-intrinsic cues but also by numerous cell-extrinsic stimuli derived from the tumor microenvironment (TME) surrounding the CSCs. In this review, we summarize the most significant discoveries regarding the metabolism of liver CSCs and highlight how the TME plays a role in regulating liver CSC metabolic plasticity. An improved understanding of the specific mechanism underlying liver CSC metabolic rewiring, as well as metabolic liver CSC–TME bidirectional crosstalk, is needed to develop valid new combinatorial therapeutic strategies. ABSTRACT: Primary liver cancer (PLC) is one of the most devastating cancers worldwide. Extensive phenotypical and functional heterogeneity is a cardinal hallmark of cancer, including PLC, and is related to the cancer stem cell (CSC) concept. CSCs are responsible for tumor growth, progression, relapse and resistance to conventional therapies. Metabolic reprogramming represents an emerging hallmark of cancer. Cancer cells, including CSCs, are very plastic and possess the dynamic ability to constantly shift between different metabolic states depending on various intrinsic and extrinsic stimuli, therefore amplifying the complexity of understanding tumor heterogeneity. Besides the well-known Warburg effect, several other metabolic pathways including lipids and iron metabolism are altered in PLC. An increasing number of studies supports the role of the surrounding tumor microenvironment (TME) in the metabolic control of liver CSCs. In this review, we discuss the complex metabolic rewiring affecting liver cancer cells and, in particular, liver CSCs. Moreover, we highlight the role of TME cellular and noncellular components in regulating liver CSC metabolic plasticity. Deciphering the specific mechanisms regulating liver CSC–TME metabolic interplay could be very helpful with respect to the development of more effective and innovative combinatorial therapies for PLC treatment.