Immunotherapy's Double-Edged Sword: Effective Against Cancer, But It Can Harm Healthy Tissue
Immunotherapy has been a major breakthrough in cancer treatment. By activating the body's own immune system to recognize and attack cancer cells, it has brought new hope to many patients with difficult-to-treat cancers. However, this therapy can sometimes cause the immune system's "brakes" to fail, leading it to attack normal tissues and triggering what are known as immune-related adverse events (irAEs).
These reactions are particularly common in patients receiving immune checkpoint inhibitors (such as PD-1/PD-L1 inhibitors and CTLA-4 inhibitors). Depending on the type of checkpoint inhibitor, approximately 20% to 40% of patients experience immune-related adverse events, and up to 25% develop severe reactions requiring hospitalization and discontinuation of cancer treatment. Currently, no FDA-approved therapies exist specifically for these side effects.
"Immune-related adverse events are a huge problem and can greatly impact quality of life for patients. In many cases, it impacts their ability to stay on immunotherapy or benefit from treatment," said Abigail Overacre-Delgoffe, Ph.D., assistant professor in the Department of Immunology at the University of Pittsburgh School of Medicine and a member of the Tumor Microenvironment Center at UPMC Hillman Cancer Center.
New Study Identifies the Culprit: Regulatory T Cells Become Unstable
Overacre-Delgoffe is the senior author of a study published October 22, 2026, in Cell. The research is the first to identify unstable immune cells as a potential driver of this inflammation.
The team focused on a type of immune cell called regulatory T cells (Tregs). Normally, Tregs suppress excessive immune responses, acting as the immune system's "brakes." But under stress or inflammatory conditions, Tregs can become unstable—a condition called "regulatory T cell fragility"—losing their ability to keep immune responses in check.
Researchers found that mice fed a Western-style diet (low in fiber, high in fat and processed carbohydrates) showed clear signs of Treg fragility during checkpoint inhibitor therapy. More importantly, Tregs collected from patients with severe immune-related adverse events showed the same instability, while cells from patients without side effects did not.
Three Intervention Strategies: Blocking a Protein, Adjusting Diet, and Supplementing Metabolites
Based on this discovery, the team tested multiple interventions, all of which showed positive results in mouse models:
- Blocking a specific immune-signaling protein: Blocking an immune-signaling protein specifically on Tregs restored their stability and reversed inflammation.
- Switching to a high-fiber diet: When mice were switched from a Western-style diet to a high-fiber diet, Tregs stabilized and the severity of adverse events dropped significantly.
- Supplementing metabolites: Giving supplements containing specific metabolites (substances produced through metabolism) also stabilized Tregs and reduced inflammation.
The study also revealed the important role of the gut microbiome. Transferring fecal microbes from mice on a Western-style diet into mice on a regular diet caused gut inflammation, while transferring fecal microbes from male mice (less susceptible to severe adverse events) into female mice reduced inflammation severity in the females. Similarly, transferring fecal microbes from patients consuming a Western-style diet into germ-free mice led to more severe immune-related adverse events.
First-of-Its-Kind Preclinical Model Paves the Way for Precision Prevention
"We were able to generate the first of its kind preclinical mouse model of adverse events that didn't require full gene knockouts," said Overacre-Delgoffe. "By combining this novel preclinical model alongside patient data, we were able to identify a very new mechanism of adverse events that hopefully will result in new targeted therapies, allowing more cancer patients to stay on treatment and out of the hospital."
The model will give researchers a platform to investigate why some patients develop severe reactions and to identify biological markers that might predict susceptibility. Future work will explore drug targets in specific tissues that could limit or eliminate these side effects without disrupting immunotherapy. Metabolite supplementation is another potential approach, although its promise here comes from experiments in mice.
"We now have some potential targets that we're going after that seem to limit immune-related adverse events without negatively impacting immunotherapy, which would be the first of its kind and is quite exciting," Overacre-Delgoffe added.
What This Means for Patients: Lifestyle May Influence Treatment Tolerance
This research suggests that diet and gut health may play an important role in tolerance to immunotherapy. While the evidence comes primarily from animal studies, a high-fiber diet and maintaining a balanced gut microbiome are beneficial for overall health regardless. Patients receiving or about to receive immunotherapy should communicate openly with their oncologist about their risk and make lifestyle adjustments under medical guidance.
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