Hypoxia and Epigenetic Reprogramming in Cancer: A Narrative Review of Mechanisms and Therapeutic Implications

Abstract

Background: Epigenetic mechanisms are fundamental regulators of gene expression and cell identity; their dysregulation contributes significantly to cancer initiation and pathological development. Tumor hypoxia, a prevalent characteristic of the tumor microenvironment that profoundly alters epigenetic regulation, results in promoting tumor aggressiveness, cancer stem cell maintenance, immune evasion, and therapeutic resistance. Objectives: This narrative review summarizes current evidence regarding hypoxia-driven epigenetic reprogramming in cancer, focusing on hypoxia-inducible factors (HIFs), DNA methylation, histone modifications, chromatin remodelling, non-coding RNAs, hypoxic memory, epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs) and therapeutic resistance. Methods: A narrative review of the literature was performed using PubMed, Scopus, and Google Scholar. Peer-reviewed studies published mainly between 2015 and 2025 were evaluated according to their relevance to hypoxia-associated epigenetic mechanisms in cancer. All articles were chosen if they were relevant to the topic and added scientific value to hypoxia associated epigenetic regulation in cancer. As this was a narrative review, there were no inclusion/ exclusion criteria or a PRISMA flow diagram.     Results: Hypoxia stabilizes HIF-1a and HIF-2α, which cooperate with multiple epigenetic regulators, including DNA methyltransferases, histone-modifying enzymes, chromatin remodelling complexes, and non–coding RNAs. These interactions promote EMT, CSC maintenance, immune escape, metastasis, and resistance to chemotherapy and immunotherapy. Emerging evidence also indicates that hypoxic memory sustains epigenetic alterations after reoxygenation, contributing to persistent malignant phenotypes.    Conclusions: Epigenetic hypoxia acts as a primary driver of cancer progression and therapeutic resistance by sustaining epigenetic reprogramming and preserving cancer stemness. Although histone deacetylase inhibitors and hypomethylating agents show therapeutic potential, their inconsistent clinical efficacy necessitates the development of optimized combination and personalized treatment strategies. Consequently, further investigation into hypoxia-driven epigenetic mechanisms is essential to enhance treatment efficacy and advance precision oncology.