Reactive Oxygen Species-Driven Cancer Therapy

Reactive oxygen species (ROS) encompass a range of oxygen-derived radicals and non-radical species that, at elevated levels, can inflict oxidative damage on cellular components. Cancer cells generally exist under higher basal oxidative stress compared with normal cells, owing to metabolic reprogramming and mitochondrial dysfunction. This vulnerability can be exploited by therapies that further elevate ROS and overwhelm antioxidant defences, notably glutathione (GSH) systems. Key modalities include photodynamic therapy (PDT), in which photosensitisers activated by light generate singlet oxygen; chemodynamic therapy (CDT), which employs in situ Fenton or Fenton-like reactions to produce hydroxyl radicals from endogenous hydrogen peroxide; and nanoparticle-based or prodrug approaches that combine ROS generation with GSH depletion or targeted delivery. These strategies aim to disrupt redox homeostasis selectively in tumours, minimise off-target toxicity and synergise with established treatments such as chemotherapy, radiotherapy or immunotherapy. Challenges include tumour heterogeneity in antioxidant capacity, limited penetration of activating stimuli and the need for spatiotemporal control of ROS bursts. Advances in stimuli-responsive materials, tumour microenvironment-activated prodrugs and combination regimens continue to broaden the therapeutic window for ROS-driven interventions.

Research from Nature Portfolio

A seminal study introduced a dual stimuli-responsive hybrid prodrug that exploits tumour acidity and elevated hydrogen peroxide to synchronously deplete glutathione and generate ROS. Upon encountering acidic pH, the prodrug releases a quinone methide moiety that scavenges GSH, while H₂O₂ triggers liberation of a cinnamaldehyde derivative that undergoes redox cycling to produce additional ROS. This two-pronged amplification of oxidative stress selectively induced cancer cell apoptosis in vitro and inhibited tumour growth in vivo, without significant harm to normal tissues. The work underscores the promise of redox-triggered prodrugs in exploiting intrinsic oxidative vulnerabilities of malignancies.

Reactive Oxygen Species-Driven Cancer Therapy publication trend

The graph below shows the total number of articles in reactive oxygen species-driven cancer therapy across all publications each year (not limited to Nature Index journals).

Technical terms

Reactive oxygen species (ROS): Chemically reactive molecules derived from oxygen, such as superoxide, hydrogen peroxide and hydroxyl radicals, capable of damaging lipids, proteins and DNA.

Glutathione (GSH): A tripeptide thiol that serves as the principal intracellular antioxidant, maintaining redox balance by neutralising ROS and supporting detoxification.

Photodynamic therapy (PDT): A treatment that employs light-activated photosensitisers to convert molecular oxygen into cytotoxic ROS within tumour tissues.

Chemodynamic therapy (CDT): A modality leveraging endogenous H₂O₂ and transition metal catalysts to generate hydroxyl radicals via Fenton or Fenton-like reactions at tumour sites.

Ferroptosis: An iron-dependent form of regulated cell death driven by lipid peroxidation and overwhelmed antioxidant defences, distinct from apoptosis and necrosis.

References

1. Amplification of oxidative stress by a dual stimuli-responsive hybrid drug enhances cancer cell death. Nature Communications (2015).
2. Endoperoxide‐enhanced self‐assembled ROS producer as intracellular prodrugs for tumor chemotherapy and chemodynamic therapy. Exploration (2024).
3. Therapeutic potentials of FexMoyS-PEG nanoparticles in colorectal cancer: a multimodal approach via ROS-ferroptosis-glycolysis regulation. Journal of Nanobiotechnology (2024).
4. Glutathione-responsive and -exhausting metal nanomedicines for robust synergistic cancer therapy. Frontiers in Bioengineering and Biotechnology (2023).