Ozone Therapy for Colorectal Cancer Remains an Unproven Idea, Review Finds

Medical ozone has been pitched for decades as a potential ally against cancer, but a new review of colorectal cancer research concludes that the evidence remains too thin to justify any routine clinical use. The analysis, published in Frontiers in Oncology, sifted through experimental and clinical studies on ozone therapy in colorectal cancer and found that while laboratory models hint at possible antitumor effects, human evidence is limited almost entirely to symptom relief rather than tumor control.

The review, led by Yanchu Li of West China Hospital of Sichuan University together with colleagues, was designed as an integrative synthesis of the colorectal cancer-specific literature. A structured search of PubMed/MEDLINE and Google Scholar, running from database inception to May 2026, identified 14 full-text reports; after five exclusions, nine studies entered the final synthesis. The authors emphasize that the field is small, heterogeneous, and dominated by preclinical work.

Ozone is a strange candidate for medicine. Inhaled, it is one of the most toxic atmospheric pollutants, reacting with airway lining fluid and pulmonary surfactant to generate reactive oxygen species and lipid oxidation products that injure the epithelial barrier. Yet when administered through non-inhalational routes, ozone reacts so rapidly with biological fluids that it never persists long enough to act like a conventional receptor-binding drug. Instead, it generates short-lived secondary messengers, chiefly hydrogen peroxide and longer-lived lipid oxidation products, which are thought to drive most of its downstream biological effects.

That redox-signaling model is central to the review’s argument. Colorectal cancer biology is already deeply entangled with oxidative stress, inflammation, and hypoxia-dependent signaling, which shape proliferation, angiogenesis, immune escape, and treatment response. A transient oxidative challenge from ozone could, in theory, push tumor cells past their redox tolerance and into apoptosis, or it could trigger an adaptive stress response that makes them harder to kill. The authors stress that the difference between these outcomes is unlikely to be uniform across colorectal cancer molecular subtypes, which differ markedly in antioxidant capacity, metabolic wiring, DNA-damage response, and stromal dependence.

The mechanistic heart of the review is the KEAP1/NRF2 signaling axis. Mild ozonization can activate this antioxidant-response pathway, which is usually interpreted as beneficial because NRF2 induces cytoprotective programs. But in colon cancer, persistent or excessive NRF2 signaling is not necessarily favorable: studies have shown that NRF2 overexpression correlates with tumor-promoting behavior, and experimental inhibition of NRF2-related survival programs can selectively kill NRF2-dependent colorectal cancer cells. In normal or injured tissue, ozone-induced NRF2 activation may help restore redox balance and limit treatment-related injury; in tumor cells with constitutively activated antioxidant machinery, the same signaling could theoretically reinforce stress tolerance and blunt therapeutic efficacy. The authors compare the required precision to the use of arsenic trioxide in leukemia treatment.

The preclinical evidence is a patchwork of proof-of-concept findings. In 1990, K. S. Zänker and colleagues indicated that ozone acts synergistically or at least additively with chemotherapy in colorectal cancer. In vitro work has since reported that ozone reduces HT29 colon-cancer cell viability, augments the effects of 5-fluorouracil and cisplatin, and suppresses inflammatory cytokines such as IL-6, IL-8, and IL-1β under lipopolysaccharide stimulation. More recent experiments in Colo-320 and Colo-741 colorectal cancer cell lines found increased cleaved caspase-3, Bax, and cytochrome c alongside decreased Bcl-2, consistent with activation of intrinsic mitochondrial apoptosis. In vivo, Kuroda and colleagues showed that ozonated water increased tumor perfusion and intratumoral oxygenation in colon-26-bearing mice and improved cisplatin efficacy, the strongest colon-model argument for adjunctive use.

But the same intervention can be protective, injurious, or reparative depending on dose, tissue context, timing, and endpoint. Himuro’s work in mouse colonic epithelium showed that intrarectal ozone caused transient epithelial injury, perturbing pathways related to DNA replication, cell cycle, and mismatch repair, followed by rapid regeneration. The review also notes that ozone has been shown to induce chromosomal breakages in human cell cultures. And on the immune front, the authors are blunt: there is still no convincing evidence that ozone therapy can convert an immune-excluded colorectal cancer into an immune-responsive state or improve immunotherapy outcomes, so immune modulation should be presented as a research hypothesis, not an established effect.

On the clinical side, the picture is thinner still. The review states plainly that there is no convincing clinical evidence that ozone therapy improves objective oncologic endpoints such as response rate, progression-free survival, or overall survival in colorectal cancer, and that randomized, tumor-specific evidence to support routine oncologic use is lacking. The available human literature instead clusters in supportive care. Clavo and colleagues reported benefit in refractory hemorrhagic radiation proctitis and persistent radiation-induced rectal bleeding after pelvic radiotherapy, and a more recent study in symptomatic cancer survivors found significant improvement in health-related quality of life and reduced treatment-related toxicity scores after ozone treatment. A 2021 review framed ozone modulation of oxidative stress as the rationale for investigating chemotherapy-induced peripheral neuropathy, and an active phase II/III trial is evaluating rectal ozone therapy for paresthesia due to that condition, which is highly relevant to oxaliplatin-based colorectal cancer treatment.

Safety considerations are fundamentally route-, dose-, and procedure-dependent. Rectal insufflation is most commonly associated with transient bloating, flatulence, and abdominal discomfort, but excessive gas volume, rapid insufflation, or high ozone concentrations may increase mechanical or oxidative mucosal injury, risks that are particularly relevant in colorectal cancer where the bowel may already be ulcerated, inflamed, irradiated, obstructed, or surgically manipulated. Ozonated water appears to have relatively low local toxicity, though rapid ozone decomposition, variable effective concentrations, mucosal irritation, and aspiration risk complicate standardization. Major autohemotherapy introduces risks related to oxidative blood exposure and extracorporeal handling, including venous-access complications, infection, vasovagal reactions, and hemolysis, particularly in susceptible individuals such as those with glucose-6-phosphate dehydrogenase deficiency; rare serious complications including ischemic events and gas embolism have also been reported. The true incidence of route-specific toxicity remains uncertain because existing studies are generally small, adverse-event reporting is inconsistent, and long-term safety data are limited.

The regulatory landscape reflects these uncertainties. In the United States, FDA regulations remain restrictive regarding medical use of ozone in the absence of demonstrated safety and effectiveness. Brazil permits ozone therapy as a complementary procedure, but the oncology indication is not among the uses currently recognized by ANVISA for ozone-emitting medical devices. Major evidence-based oncology supportive-care guidelines, including ASCO guidance for chemotherapy-induced peripheral neuropathy and MASCC/ISOO guidance for cancer therapy-related mucositis, do not currently recommend ozone as standard care. As of August 2026, registered ongoing oncology-related studies focus primarily on supportive care and treatment-related toxicities rather than direct antitumor efficacy, and no currently identified active trial is designed to establish an effect on objective tumor response, progression-free survival, or overall survival. The authors conclude that medical ozone should presently be regarded as an investigational adjunct in oncology, pending adequately powered randomized trials with standardized exposure protocols, oncologic efficacy endpoints, and long-term safety assessment.

Subject of Research: Ozone therapy as an investigational adjunct in colorectal cancer

Article Title: Ozone therapy in colorectal cancer

Article References: Li, Y., Pu, R., Yang, S., Chen, H., & Zhang, X. (2026). Ozone therapy in colorectal cancer. Frontiers in Oncology, 16, Article 1925327. https://doi.org/10.3389/fonc.2026.1925327

Image Credits: AI Generated

DOI: 10.3389/fonc.2026.1925327

Keywords: colorectal cancer, ozone therapy, medical ozone, NRF2, oxidative stress, preclinical evidence, supportive care, chemotherapy-induced peripheral neuropathy, tumor microenvironment, hypoxia, safety, clinical trials