Oxidative Stress and Redox Signaling in Cancer Biology

Oxidative stress arises when the generation of reactive oxygen species (ROS) exceeds the capacity of cellular antioxidant defences, leading to damage of DNA, proteins and lipids. In cancer biology, a persistent imbalance in redox homeostasis not only contributes to oncogenic transformation by inducing mutagenesis and genomic instability but also creates a unique metabolic environment that supports tumour growth. Far from being a mere by-product of metabolism, ROS act as second messengers in redox signaling pathways that regulate proliferation, survival, autophagy and angiogenesis. Key transcription factors and enzymes—including nuclear factor erythroid 2-related factor 2 (Nrf2), Kelch-like ECH-associated protein 1 (Keap1) and BACH1—sense fluctuations in the redox landscape and orchestrate adaptive programmes of gene expression and protein turnover. Tumour cells exploit these pathways to withstand hostile microenvironments, resist therapy and modulate immune responses. At the same time, pharmacological modulation of ROS levels, either by inhibiting antioxidant defences or by promoting ROS accumulation, is emerging as a promising approach to trigger selective cancer cell death. Understanding the dual roles of oxidative stress as both promoter and suppressor of malignancy is pivotal for the development of redox-based therapeutic strategies.

Research from Nature Portfolio

Recent studies have shed light on the non-canonical functions of Nrf2 in the tumour microenvironment. Work exploring the role of Nrf2 in immune cells revealed that, independently of its classical antioxidant response element, Nrf2 can bind proximal to proinflammatory cytokine genes in macrophages and inhibit their transcription by blocking RNA polymerase II recruitment. This redox-independent mechanism underscores how Nrf2 not only defends against oxidative damage in cancer cells but also shapes inflammatory signalling and immune surveillance in growing tumours. Such findings broaden the conventional view of Nrf2 as a cytoprotective factor and highlight its multifaceted contributions to tumour biology and therapeutic resistance.

Oxidative Stress and Redox Signaling in Cancer Biology publication trend

The graph below shows the total number of articles in oxidative stress and redox signaling in cancer biology across all publications each year (not limited to Nature Index journals).

Technical terms

Reactive oxygen species (ROS): chemically reactive molecules derived from oxygen metabolism that function in both cell signalling and oxidative damage.

Oxidative stress: a cellular state in which ROS exceed antioxidant capacity, causing potential harm to biomolecules.

Redox signaling: regulatory processes in which reversible oxidation–reduction reactions modulate protein activity and gene expression.

Nrf2 (nuclear factor erythroid 2-related factor 2): a master transcription factor that induces antioxidant and detoxification enzymes in response to oxidative or electrophilic stress.

BACH1: a transcriptional repressor of antioxidant response genes that is targeted for degradation under oxidative conditions.

Degron: a specific amino-acid sequence or structural motif within a protein that signals for its ubiquitin-mediated degradation.

Ubiquitination: a post-translational modification in which ubiquitin molecules are covalently attached to a substrate, marking it for proteasomal degradation.

References

1. Recognition of BACH1 quaternary structure degrons by two F-box proteins under oxidative stress. Cell (2024).
2. Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription. Nature Communications (2016).
3. The Keap1-Nrf2 pathway: Mechanisms of activation and dysregulation in cancer. Redox Biology (2013).
4. ROS and ROS‐Mediated Cellular Signaling. Oxidative Medicine and Cellular Longevity (2016).
5. The Chemistry of Reactive Oxygen Species (ROS) Revisited: Outlining Their Role in Biological Macromolecules (DNA, Lipids and Proteins) and Induced Pathologies. International Journal of Molecular Sciences (2021).
6. ROS in cancer therapy: the bright side of the moon. Experimental & Molecular Medicine (2020).