Influence of Hypoxia on Tumor Heterogeneity, DNA Repair, and Cancer Therapy: From Molecular Insights to Therapeutic Strategies

Abstract

Hypoxia, characterized by a reduction in tissue oxygen levels, is a hallmark of many solid tumors and affects a range of cellular processes, including DNA repair. In low-oxygen conditions, cancer cells often suppress key DNA repair pathways such as homologous recombination (HR), leading to the accumulation of DNA damage and increased genomic instability. These changes not only drive tumor progression but also contribute to resistance against conventional therapies. Hypoxia significantly reduces the effectiveness of oxygen-dependent treatments, including radiotherapy and many chemotherapeutic agents. To address this limitation, bioreductive drugs have been developed that become selectively activated in hypoxic environments, providing targeted cytotoxic effects within oxygen-deprived tumor regions. Additionally, the rapid growth of tumors often results in disorganized and inefficient vasculature, further impairing the delivery of oxygen and therapeutic agents. This review explores the molecular mechanisms by which hypoxia disrupts DNA repair and contributes to treatment resistance. It also presents emerging therapeutic strategies aimed at targeting the hypoxic tumor microenvironment to improve treatment efficacy and patient outcomes.

Keywords: DNA repair; cancer; cancer therapy; hypoxia; hypoxia-inducible factors (HIFs); hypoxia-targeted therapy; therapeutic resistance; tumor heterogeneity; tumor microenvironment.

Figure 1

Key Biological Consequences of Hypoxia in Tumor Cells.

Figure 2

The link between tumor oxygen levels and therapy resistance. Oxygen decreases with distance from blood vessels, leading to hypoxia and necrosis. Hypoxia-inducible factors (HIFs) drive adaptations that enhance survival. As hypoxia increases, resistance to chemotherapy and radiation rises, making treatment less effective.

Figure 3

Illustration of the activation of ATM and ATR pathways in response to hypoxia-induced replication stress. ATR is recruited via RPA (Replication Protein A)-coated single-stranded DNA and its co-factor ATRIP. ATM, possibly through a non-canonical mechanism, promotes HIF-1α stabilization via CHK2, while ATR enhances HIF-1α mRNA translation. Together, these responses contribute to the activation of hypoxia-responsive gene expression.

Figure 4

DNA damage response is regulated by key kinases ATM and ATR, which are activated under stress conditions such as hypoxia. These kinases activate checkpoint proteins CHK1/2, leading to the phosphorylation of the tumor suppressor protein p53. In response, P53 initiates cellular processes, including DNA repair, cell cycle arrest, apoptosis, and senescence. Proteins like MLH1, NBN, and Ku70/Ku80 support damage-sensing and repair pathways, maintaining genomic stability.

Figure 5

The simplified representation of direct and HIF-dependent effects driven by hypoxic conditions in cancer cell microenvironment. Insufficient supply of oxygen induces mitochondrial dysfunction, UPR, and reprograms cellular bioenergetics toward glycolysis. HIF-1α, no longer degraded as a result of ubiquitin detachment in hypoxia, upregulates various target genes interacting with their hypoxia-response elements (HREs), supporting cancer cells in proliferation, survival, and increasing their invasiveness. It leads to resistance to a range of anticancer therapies, which is associated with treatment failures, recurrences, and overall reduces patient’s life expectancy as well as quality.