Metabolic Plasticity and Cancer Stem Cell Metabolism: Exploring the Glycolysis-OXPHOS Switch as a Mechanism for Resistance and Tumorigenesis
Li Qing Keoh, Ching‐Feng Chiu, Thamil Selvee Ramasamy
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.