Cancer stem cells: landscape, challenges and emerging therapeutic innovations

Abstract Cancer stem cells (CSCs) constitute a highly plastic and therapy-resistant cell subpopulation within tumors that drives tumor initiation, progression, metastasis, and relapse. Their ability to evade conventional treatments, adapt to metabolic stress, and interact with the tumor microenvironment makes them critical targets for innovative therapeutic strategies. Recent advances in single-cell sequencing, spatial transcriptomics, and multiomics integration have significantly improved our understanding of CSC heterogeneity and metabolic adaptability. Metabolic plasticity allows CSCs to switch between glycolysis, oxidative phosphorylation, and alternative fuel sources such as glutamine and fatty acids, enabling them to survive under diverse environmental conditions. Moreover, interactions with stromal cells, immune components, and vascular endothelial cells facilitate metabolic symbiosis, further promoting CSC survival and drug resistance. Despite substantial progress, major hurdles remain, including the lack of universally reliable CSC biomarkers and the challenge of targeting CSCs without affecting normal stem cells. The development of 3D organoid models, CRISPR-based functional screens, and AI-driven multiomics analysis is paving the way for precision-targeted CSC therapies. Emerging strategies such as dual metabolic inhibition, synthetic biology-based interventions, and immune-based approaches hold promise for overcoming CSC-mediated therapy resistance. Moving forward, an integrative approach combining metabolic reprogramming, immunomodulation, and targeted inhibition of CSC vulnerabilities is essential for developing effective CSC-directed therapies. This review discusses the latest advancements in CSC biology, highlights key challenges, and explores future perspectives on translating these findings into clinical applications.