Key Takeaways & Executive Findings
- •• • CSCs exhibit elevated mitochondrial activity and fatty acid oxidation, contrasting with bulk tumor glycolysis, supporting quiescence and stress tolerance; this metabolic flexibility is a target for differentiation therapy. • • Selective suppression of proteasome function in CSCs, as evidenced by hypersensitivity to proteasomal inhibition in glioma-derived CSCs (Yoo et al., EMBO Rep 2017), suggests proteasome inhibitors could selectively eradicate CSCs. • • Metabolic intermediates (acetyl-CoA, succinate, lactate) act as epigenetic cofactors, linking nutrient availability to chromatin remodeling and transcriptional plasticity, offering targets for epigenetic drugs. • • The tumor microenvironment, including hypoxia and cytokine signaling, modulates CSC metabolism and reinforces stemness, implying that anti-stromal therapies may disrupt CSC maintenance.
Abstract
Cancer stem cells (CSCs) represent a minor but highly adaptable subpopulation within tumors that drives long-term growth, metastasis, and therapy resistance. Their ability to survive and regenerate under metabolic and therapeutic stress relies on a unique integration of energy flexibility, redox balance, and proteostatic programs. While bulk tumor cells typically favor aerobic glycolysis and high protein turnover, CSCs often exhibit elevated mitochondrial activity, fatty acid oxidation, and selective suppression of proteasome function. These metabolic features support quiescence, stress tolerance, and self-renewal. Beyond energy production, metabolic intermediates such as acetyl-CoA, succinate, and lactate serve as epigenetic cofactors, linking nutrient availability to chromatin remodeling and transcriptional plasticity. Reactive oxygen species and antioxidant responses further tune this balance, shaping the transition between glycolytic and oxidative CSC states. These intrinsic programs are continuously influenced by the tumor microenvironment, where hypoxia, cytokine-driven signaling, and metabolic coupling with stromal and immune cells modulate CSC metabolism and reinforce stemness. Despite rapid progress, major conceptual and methodological gaps still limit our understanding of CSC metabolism. This review highlights these unresolved issues and outlines key contextual factors—including tumor-intrinsic, microenvironmental, systemic, and metastatic cues—that shape CSC metabolism and help explain the heterogeneity of CSC phenotypes and therapeutic responses.
1. Introduction
Despite decades of research, cancer stem cells (CSCs) remain a formidable clinical challenge due to their inherent plasticity and resistance to conventional therapies. Existing therapeutic strategies targeting bulk tumor proliferation often fail to eradicate the quiescent CSC population, leading to relapse and metastasis. The metabolic and proteostatic adaptations that enable CSCs to survive under stress are not fully understood, and current in vitro models inadequately recapitulate the complex tumor microenvironment, hindering drug development.
This review addresses these bottlenecks by synthesizing recent findings on CSC metabolism, emphasizing the dynamic interplay between energy production, redox balance, and proteostasis. It highlights how metabolic intermediates influence epigenetic regulation, providing a mechanistic link between nutrient availability and stemness. By outlining key contextual factors—tumor-intrinsic, microenvironmental, systemic, and metastatic—this work offers a framework for developing targeted therapies that disrupt CSC-specific vulnerabilities, potentially overcoming resistance and improving patient outcomes.
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Tylichova Zuzana, et al. (2026). Metabolic and Proteostatic Plasticity of Cancer Stem Cells: Integrating Energy Flexibility, Redox Balance, and Epigenetic Remodeling in Tumor Progression and Therapy Resistance. Stem Cell Research & Therapy. https://doi.org/10.1186/s13287-026-05014-4
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Frequently Asked Questions
What are the specific metabolic vulnerabilities of CSCs that can be targeted therapeutically without affecting normal stem cells?
CSCs exhibit elevated mitochondrial activity and fatty acid oxidation, and are hypersensitive to proteasomal inhibition, as shown in glioma-derived CSCs (Yoo et al., EMBO Rep 2017). These features can be selectively targeted using inhibitors of fatty acid oxidation or proteasome inhibitors, potentially sparing normal quiescent stem cells that rely on glycolysis.
How does the tumor microenvironment influence CSC metabolism and stemness, and what are the implications for drug resistance?
Hypoxia and cytokine signaling in the tumor microenvironment modulate CSC metabolism, promoting a shift towards oxidative phosphorylation and fatty acid oxidation, which supports stemness and therapy resistance. This metabolic coupling with stromal and immune cells suggests that combining anti-angiogenic or anti-inflammatory agents with metabolic inhibitors could disrupt CSC maintenance.
What are the methodological challenges in studying CSC metabolism, and how can they be overcome?
Current 2D culture conditions do not recapitulate the 3D tumor microenvironment, leading to altered metabolic profiles (Rybkowska et al., Cells 2023). Advanced 3D models and in vivo imaging are needed to accurately assess CSC metabolism and drug responses.
Can metabolic intermediates such as acetyl-CoA and lactate serve as biomarkers for CSC presence or therapeutic response?
Yes, these intermediates are elevated in CSCs and can be detected in patient samples, potentially serving as biomarkers for CSC load and monitoring treatment efficacy. However, validation in clinical cohorts is required.
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