In recent years, oncological research has changed the way we understand reactive oxygen species (ROS). For decades, these free radicals were seen solely as harmful agents, responsible for cellular deterioration and the development of multiple diseases. However, a recent study published in Cell Stress Chaperones in 2025 by Ma, Wang, Li, Xu, and Tan (researchers from the Heilongjiang Provincial Hospital, Harbin Medical University, and Heilongjiang University of Chinese Medicine) has shown that the reality is much more complex. ROS are not merely destructive; they also function as indispensable biological signals that guide the fate of cells. This dual nature, both protective and harmful, makes ROS a central element of tumor biology and, at the same time, a therapeutic target of great interest.

ROS are unstable molecules derived from oxygen. Examples include superoxide (O₂⁻), hydrogen peroxide (H₂O₂), and the hydroxyl radical (OH). They are generated naturally within cells, especially in the mitochondria, although specialized enzymes and external factors such as ultraviolet radiation also contribute. From a technical perspective, their relevance lies in the fact that they readily react with other molecules, acting as messengers in signaling processes that control proliferation, inflammation, and programmed cell death, but also damaging proteins, lipids, and DNA when they accumulate excessively.

Cancer, however, has learned to manipulate this balance. Tumor cells increase their internal ROS levels to a point that stimulates growth, facilitates the formation of blood vessels, and promotes the ability to invade tissues. At the same time, they reinforce their antioxidant defenses to avoid self-destruction. This strategy is called redox adaptation, a fine-tuned adjustment that allows tumors to survive in adverse environments such as hypoxia or chronic inflammation. Notably, the function of ROS depends not only on their amount, but also on the place and time in which they are produced. Brief peaks in certain pathways can drive proliferation, whereas prolonged exposure may induce apoptosis.

This balance is reflected in several fundamental biological pathways. NF-κB is a transcription factor that regulates genes related to inflammation and cell survival. In the context of cancer, when ROS activate it, a vicious cycle of chronic inflammation and resistance to cell death occurs, allowing the tumor to grow and become more aggressive. HIF-1, on the other hand, is a protein activated under conditions of low oxygen (hypoxia), typical of the tumor environment. ROS promote its stabilization, and with it, the stimulation of new blood vessel formation and the adjustment of cellular metabolism to sustain tumor growth. Finally, NRF2 functions as a “master switch” of antioxidant defenses. In healthy cells, it protects against oxidative damage; but in tumors, its continuous activation strengthens the cancer’s ability to resist treatments and facilitate metastasis. Put more simply, these three regulators are like molecular switches: under normal conditions they maintain order, but in cancer, when inappropriately activated, they become accomplices of the disease.

The study pays particular attention to cancer stem cells, a subpopulation with great capacity to regenerate the tumor after treatment. These cells maintain unusually low levels of ROS thanks to mechanisms that increase the production of glutathione, the cell’s most powerful antioxidant. Variants of molecules such as CD44 or the expression of CD13 in liver tumors enable this control. By reducing oxidative stress, these cells resist chemotherapies that depend precisely on ROS to eliminate malignant cells. Inhibiting these mechanisms can raise ROS levels in cancer stem cells and increase their vulnerability, offering a relevant therapeutic opportunity.

Beyond individual cells, ROS also shape the tumor microenvironment. Interactions with fibroblasts, blood vessels, and immune cells generate a setting where hypoxia and acidity favor immune evasion. Interestingly, intermediate levels of ROS can enhance the function of T lymphocytes, boosting the antitumor response, while very high concentrations cause exhaustion and loss of effectiveness. Consequently, ROS determine not only the fate of the tumor but also the ability of the immune system to confront it.

Figure 1. The balance between the production of reactive oxygen species and antioxidant mechanisms defines a critical point in cancer biology, where the same process may sustain cellular homeostasis or drive malignant transformation depending on the context.

On this basis, the authors propose different therapeutic approaches. One of them is to dismantle the tumor’s antioxidant defenses. By blocking glutathione synthesis with compounds such as buthionine sulfoximine, resistance is reversed in experimental models, increasing chemotherapy effectiveness. Another strategy consists of deliberately pushing oxidative stress to lethal levels for tumor cells. Examples such as APR-246, which interferes with p53 and glutathione metabolism, have shown encouraging results in combination with conventional drugs. In addition, nanomaterials capable of capturing glutathione within the tumor and releasing drugs selectively are being investigated, multiplying treatment effects without harming healthy tissue.

A third, more complex approach is NRF2 inhibition. In preclinical models, its blockade increases tumor sensitivity to chemotherapy. However, since NRF2 also protects healthy tissues, this strategy requires targeted delivery mechanisms to minimize adverse effects.

Taken together, the results of this work do not offer a single or definitive solution. Rather, they propose a new way of understanding cancer: not only as a set of mutations, but as a system dependent on an unstable redox balance. From this perspective, the challenge of modern oncology is to learn how to strategically alter this balance, turning what today is a tumor strength into its main vulnerability. To achieve this, it will be essential to develop biomarkers capable of measuring the oxidative state of cancer in real time, as well as designing precision therapies able to modulate ROS without compromising the integrity of normal tissues.

In conclusion, cancer lives permanently on the edge of what is tolerable, sustained by a delicate balance between oxidation and antioxidant defense. Understanding that balance and manipulating it precisely opens a promising path toward more effective and personalized therapies, in which ROS would shift from being allies of the tumor to becoming tools against it.

Main reference:

Ma, N., Wang, Y., Li, X., Xu, M., & Tan, D. (2025). Reactive oxygen species in cancer: Mechanistic insights and therapeutic innovations. Cell stress & chaperones, 30(5), 100108. https://doi.org/10.1016/j.cstres.2025.100108

Other references:

Cheung, E. C., & Vousden, K. H. (2022). The role of ROS in tumour development and progression. Nature reviews. Cancer, 22(5), 280–297. https://doi.org/10.1038/s41568-021-00435-0

Yang, B., Chen, Y., & Shi, J. (2019). Reactive Oxygen Species (ROS)-Based Nanomedicine. Chemical reviews, 119(8), 4881–4985. https://doi.org/10.1021/acs.chemrev.8b00626

Gorrini, C., Harris, I. S., & Mak, T. W. (2013). Modulation of oxidative stress as an anticancer strategy. Nature reviews. Drug discovery, 12(12), 931–947. https://doi.org/10.1038/nrd4002