Dynamic changes in the metabolic network and signalling pathways of cancer stem cells in therapy resistance.

Cancer stem cells (CSCs) play a pivotal role in therapeutic resistance, metastasis, and tumour recurrence. During treatment, these cells undergo dynamic changes that enable survival and metabolic adaptation, leading to poor clinical outcomes. CSCs are capable of developing resistance to drugs by alterations in the metabolic and signalling pathways. They exhibit metabolic adaptations that enable therapy resistance, tumour recurrence, and metastasis. These adaptations involve shifts in glycolysis, oxidative phosphorylation (OXPHOS), lipid and amino acid metabolism, mitochondrial dynamics, and interactions with the tumour microenvironment to support energy production. Depending on the biological contexts and the energy needs, CSCs can switch to different metabolic phenotypes. CSCs drive energy production and biogenesis via glycolysis in hypoxic conditions. OXPHOS is essential for sustaining cell dormancy, survival and carcinogenesis. In addition to glycolysis and OXPHOS, CSCs employ lipid metabolism for energy production via fatty acid oxidation and amino acids metabolism via glutamine metabolism promoting redox balancing and epigenetic modifications. Taken together, this metabolic plasticity facilitates CSC survival and treatment resistance. Besides, CSCs are capable of metabolically rewiring their niche to evade apoptosis, enhance DNA repair, and promote immune evasion, which are considered hallmarks of drug resistance and cancer relapse. An in-depth understanding of the metabolic network and signalling pathways of CSCs may help in developing combination or targeted therapies against them, thereby increasing the potential to formulate effective treatment approaches for the complete eradication of cancer/CSCs. This review addresses dynamic changes in the CSCs' metabolism and signalling leading to the development of drug-resistance phenotype, causing survival and relapse in the tumours. Therapeutic strategies targeting CSC metabolism and signalling via metabolic modulators and stemness inhibitor were discussed. Overall, CSC metabolic adaptation promotes drug resistance and tumour proliferation. Hence targeting these metabolic adaptations offers new perspective for the elimination of CSCs and enhanced therapy.