Advances in Cancer Prevention
Open Access

Cancer stem cells; Metabolomics; Metabolic vulnerabilities; Glycolysis; Oxidative phosphorylation; Glutamine metabolism

Introduction

Cancer stem cells (CSCs) represent a subpopulation of tumor cells with the ability to self-renew, differentiate, and drive tumor progression and metastasis [1]. These cells contribute significantly to tumor heterogeneity, therapeutic resistance, and disease recurrence, making them a crucial target for cancer treatment. Unlike bulk tumor cells, CSCs exhibit distinct metabolic adaptations that enable them to survive under adverse conditions, including nutrient deprivation, oxidative stress, and hypoxia [2]. Metabolomics, the large-scale study of small-molecule metabolites within cells, tissues, and biofluids, has emerged as a powerful approach for identifying the unique metabolic features of CSCs. Research has shown that CSCs rely on flexible metabolic pathways, including glycolysis, oxidative phosphorylation (OXPHOS), glutamine metabolism, and lipid biosynthesis, to maintain their stemness and evade therapeutic interventions. The ability of CSCs to dynamically switch between aerobic glycolysis (Warburg effect) and mitochondrial respiration provides them with metabolic plasticity, allowing survival in different tumor microenvironments [3].

Understanding the metabolomic landscape of CSCs is essential for identifying novel therapeutic vulnerabilities and developing targeted treatments that disrupt key metabolic pathways. Metabolic inhibitors targeting glucose metabolism, mitochondrial function, lipid synthesis, and redox homeostasis have shown promise in preclinical studies. However, challenges such as tumor heterogeneity, metabolic adaptability, and the influence of the tumor microenvironment must be addressed to translate these findings into effective clinical strategies [4]. This review explores the metabolomic characteristics of CSCs, highlighting their unique metabolic dependencies, potential therapeutic targets, and emerging strategies for CSC-directed cancer treatment. By integrating metabolomics with other omics-based approaches, researchers aim to develop precision medicine strategies that selectively eliminate CSCs while minimizing toxicity to normal stem cells [5].

Discussion

The metabolic adaptations of cancer stem cells (CSCs) play a crucial role in their ability to sustain tumor growth, evade immune surveillance, and resist conventional therapies. Unlike bulk tumor cells, which primarily rely on either glycolysis or oxidative phosphorylation (OXPHOS), CSCs exhibit remarkable metabolic plasticity, allowing them to switch between these pathways in response to micro environmental changes [6]. This adaptability poses a significant challenge for therapeutic targeting but also reveals unique metabolic vulnerabilities that can be exploited for treatment. Many CSCs exhibit enhanced aerobic glycolysis, a phenomenon known as the Warburg effect, where they preferentially utilize glucose for ATP production even in the presence of oxygen. Increased expression of glycolytic enzymes such as hexokinase 2 (HK2), pyruvate kinase M2 (PKM2), and lactate dehydrogenase A (LDHA) supports rapid energy generation and biosynthetic precursor production. Targeting glycolytic regulators with inhibitors like 2-deoxyglucose (2-DG) and dichloroacetate (DCA) has shown promise in disrupting CSC metabolism [7].

Some CSCs, particularly those found in low-glucose or oxygen-limited environments, preferentially utilize OXPHOS for energy production. Studies have demonstrated that CSCs often have enhanced mitochondrial biogenesis and increased reliance on fatty acid oxidation (FAO) to maintain their stem-like properties. Inhibitors of mitochondrial respiration, such as metformin and oligomycin, have been explored as potential CSC-targeting agents. CSCs exhibit a high dependency on glutamine metabolism, which serves as a key carbon and nitrogen source for anabolic processes. Glutaminase inhibitors such as CB-839 have demonstrated potential in disrupting glutamine-dependent CSC survival. Similarly, branched-chain amino acid (BCAA) metabolism has been linked to CSC maintenance, suggesting that amino acid depletion strategies may weaken CSC function [8].

Lipid metabolism plays a critical role in CSC survival, particularly in oxidative stress management and energy storage. Increased fatty acid synthesis and uptake, regulated by enzymes like fatty acid synthase (FASN) and stearoyl-CoA desaturase 1 (SCD1), contribute to CSC proliferation and chemoresistance. Additionally, reactive oxygen species (ROS) homeostasis is crucial for CSC maintenance, as excess ROS can induce differentiation or apoptosis. Antioxidant pathways, including glutathione and NADPH production, help CSCs counteract oxidative stress, making redox modulators attractive therapeutic targets. Combination Therapy Approaches: Given CSCs' ability to switch metabolic states, combination therapies targeting both glycolysis and OXPHOS may be more effective than single-agent treatments. Dual inhibition of glycolysis (2-DG) and mitochondrial respiration (metformin) has shown synergistic effects in preclinical models [9].

Several metabolic inhibitors targeting glucose, lipid, and amino acid metabolism are currently being evaluated in clinical trials for their efficacy in eliminating CSC populations. The metabolic flexibility of CSCs is strongly influenced by interactions with the tumor microenvironment (TME). Hypoxia, immune cell infiltration, and nutrient availability play crucial roles in shaping CSC metabolism, making it necessary to consider TME factors when designing metabolic therapies. CSCs can develop adaptive resistance to metabolic inhibitors by reprogramming their energy metabolism. Overcoming this challenge requires personalized medicine approaches that integrate multi-omics profiling to identify patient-specific metabolic vulnerabilities [10].

Conclusion

The metabolomic study of CSCs has revealed distinct metabolic dependencies that contribute to their survival, therapy resistance, and tumor recurrence. By targeting key metabolic pathways, such as glycolysis, OXPHOS, glutamine metabolism, and lipid biosynthesis, new therapeutic strategies can be developed to selectively eliminate CSCs. However, the challenges of metabolic plasticity, tumor microenvironment influences, and adaptive resistance must be addressed to optimize CSC-targeting therapies. Future research should focus on integrating metabolomics with genomics and proteomics to develop precision medicine strategies that disrupt CSC metabolism while minimizing toxicity to normal cells.

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