Cited by 66Cancer, Hypoxia, and MetabolismCancer Cells and MetastasisMetabolism, Diabetes, and Cancer

Metabolic plasticity and cancer stem cell metabolism: Exploring the glycolysis-OXPHOS switch as a mechanism for resistance and tumorigenesis

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Keoh, Li Qing, Chiu, Ching-Feng, Ramasamy, Thamil Selvee·2025·Stem Cell Reviews and Reports

Abstract

Metabolic plasticity is a hallmark of cancer, enabling tumour cells to grow and adapt to microenvironmental stress, eventually contributing to tumour heterogeneity. Although glycolysis-oxidative phosphorylation (OXPHOS) switch plays a pivotal role, emerging evidence highlights OXPHOS as an essential mechanism for cancer survival, particularly during metastasis and therapeutic stress, underscoring the complexities underlying metabolic plasticity and tumour heterogeneity. The role of glycolysis-OXPHOS switch in cancer stem cells (CSCs), a highly aggressive and drug-resistant population frequently enriched in response to the stress of tumour growth and pressure from microenvironmental or therapeutic cues, remains an open question with therapeutic interventions yielding mixed outcomes. While some strategies suppress CSC activity, others inadvertently promote resistance and tumour aggressiveness, thus contributing to treatment failure and relapse. This review critically examines the role of glycolysis-OXPHOS switch as a gatekeeper of tumorigenesis which influences CSC plasticity and resistance. By dissecting these metabolic dynamics, it aims to inform novel therapeutic strategies, emphasising tailored approaches to target CSC plasticity and improve cancer treatment outcomes. 1. Cancer cells undergo glycolysis-OXPHOS switch for survival and growth via the modulation of the gene regulatory network and metabolic enzymes. 2. OXPHOS emerges as a preferred metabolic strategy in certain cancers and CSCs, particularly under metabolic stress, nutrient deprivation or microenvironmental cues. 3. Conventional cancer therapies can induce metabolic reprogramming from glycolysis to OXPHOS, contributing to treatment resistance and the enrichment of more aggressive subpopulations within tumours. 4. CSCs display marked metabolic plasticity, with some relying on glycolysis to drive proliferation, while others favour OXPHOS to sustain stemness and adapt to therapeutic or metabolic stress. 5. Therapeutic stress can trigger a metabolic switch in CSCs from glycolysis to OXPHOS, a double-edged sword that may either sensitise cells to oxidative damage or enhance resistance, promoting survival and relapse. 6. Metabolic heterogeneity and adaptability of CSCs present significant challenges for designing metabolic therapy, as CSCs can dynamically reprogram their metabolism in response to targeted interventions.

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  1. [8]Phan, L. M., Yeung, S. C., & Lee, M. H. (2014). Cancer metabolic reprogramming: Importance, main features, and potentials for precise targeted anti-cancer therapies. Cancer Biology & Medicine, 11 (1), 1–19. 24738035 PMC3969803
  2. [68]Palorini, R., et al. (2014). Energy metabolism characterization of a novel cancer stem cell-like line 3AB-OS. Journal of Cellular Biochemistry, 115 (2), 368–379. 24030970

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Authors
Keoh, L. Q., Chiu, C.-F., & Ramasamy, T. S.
Affiliations
  • University of Malaya (MY)
  • Taipei Medical University-Shuang Ho Hospital (TW)
Corresponding author
Ramasamy, Thamil Selvee
Venue
Stem Cell Reviews and Reports
Published
2025-08-29
Volume
21
Issue
8
Pages
2446-2468
ISSN
  • 1550-8943 (ISSN-L)
  • 2629-3269
  • 2629-3277
OpenAlex
W4413832697
Cited by
66
References
90
Citations by year
2026: 60 · 2025: 6
FWCI
6.80
Type
journal article
Language
en
Open access
Locations
  • Stem Cell Reviews and Reports (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
Funders
Universiti Malaya
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
cancer stem cells, metabolic plasticity, oxidative phosphorylation, carcinogenesis, drug resistance, tumor heterogeneity, metabolic reprogramming, tumor microenvironment, metabolic therapy, tumor recurrence
MeSH terms
Animals, Glycolysis, Humans, Neoplasms, Oxidative Phosphorylation, Neoplastic Stem Cells, Drug Resistance, Neoplasm, Tumor Microenvironment, Carcinogenesis

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