Hypoxia-Inducible Factors as Guardians of Cancer Stem Cell Fate: Implications for Novel Therapies.

Cancer stem cells (CSCs) represent a dynamic, therapy-refractory subpopulation that fuels tumor initiation, metastasis, and relapse through remarkable self-renewal capacity and phenotypic plasticity. Extensive evidence has established that hypoxia-inducible factors (HIFs), especially HIF-1α and HIF-2α, are key regulators of CSC behavior within the hypoxic tumor microenvironment (TME) across diverse malignancies, including breast cancer, glioblastoma, and colorectal carcinoma. Under hypoxic conditions, HIFs stabilization orchestrates stemness maintenance, epithelial-mesenchymal transition (EMT), immune evasion, and metabolic reprogramming. Concurrently, HIF activity upregulates efflux transporters and anti-apoptotic genes, thereby contributing to resistance against chemotherapy and radiotherapy. This review integrates recent advances in HIF-CSC crosstalk, with particular emphasis on interactions with core pluripotency networks (Oct4, Sox2, Nanog), therapy-induced CSC enrichment, and hypoxia-driven immune suppression. We further highlight current limitations and prospects of HIF-targeted strategies, including isoform-specific inhibitors and combination regimens. By addressing existing knowledge gaps, this work provides a comprehensive framework to guide the development of next-generation therapies aimed at durable CSC eradication and improved clinical outcomes in hypoxia-driven cancers.