10/22/2026
A University of Pittsburgh study revealed that unstable immune cells, diet and the microbiome are all drivers of severe side effects affecting up to 40% of immunotherapy patients
PITTSBURGH –
Researchers at the University of Pittsburgh identified the unstable immune cells that drive serious side effects of cancer immunotherapy and showed that diet and the gut microbiome influence how severe those side effects become. The findings were published Oct. 22, 2026, in the journal Cell.
Key Takeaways
- University of Pittsburgh researchers created a diet-based mouse model to study immune-related adverse events, a serious side effect of immune checkpoint inhibitor therapy that affects up to 40% of patients and has no FDA-approved treatment.
- The study found that feeding mice a Western-style diet low in fiber and high in fat before and during immune checkpoint inhibitor treatment caused regulatory T cell fragility, a key driver of the side effect.
- Researchers observed the same regulatory T cell fragility in immunotherapy patients with severe immune-related adverse events but not in patients without the side effect.
- Blocking an immune signaling protein on regulatory T cells, switching mice to a high-fiber diet, or giving metabolite supplementation restored cell stability and reduced the severity of adverse events.
- Fecal microbiome transfers between mice on different diets and from patients on a Western-style diet to germ-free mice showed that gut microbiome composition influences the severity of immune-related adverse events.
Immune checkpoint inhibitors, a type of cancer immunotherapy, work by releasing the brakes on T cells, immune cells that can attack tumors. But that same mechanism can cause T cells to attack healthy tissue, resulting in a toxic side effect called immune-related adverse events. Depending on the drug, 20% to 40% of patients experience these events, and up to 25% are severe enough to require hospitalization and ending treatment. There are no treatments approved by the U.S. Food and Drug Administration for immune-related adverse events.
"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 senior author Abigail Overacre-Delgoffe, Ph.D., assistant professor in the Department of Immunology at Pitt’s School of Medicine and member of the Tumor Microenvironment Center at the UPMC Hillman Cancer Center.
First-of-its-kind mouse model links diet to immunotherapy side effects
Until now, animal models have struggled to replicate the complexity of immune-related adverse events in humans.
"Most existing mouse models relied on genetically modified mice or experimental conditions that didn't really capture the variability we see in patients," said lead author Dipyaman Patra, Ph.D., a postdoctoral associate in Overacre-Delgoffe’s lab. "This got us thinking about whether common lifestyle factors, particularly diet and the gut microbiome, could influence the host immune system even before immunotherapy begins."
The team fed mice a “Western-style diet”—low in fiber and high in fat and processed carbohydrates—for two weeks before and during immune checkpoint inhibitor treatment. The approach reproduced many immune and microbiome features seen in human patients, without requiring genetically altered mice.
"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."
Regulatory T cell fragility identified as key driver of immunotherapy side effects
Mice on the Western–style diet developed immune-related inflammation and showed signs of “fragile” regulatory T cells, immune cells that normally suppress inflammation. Under stress, these cells enter an unstable state called regulatory T cell fragility.
The team found the same fragility in regulatory T cells taken from immunotherapy patients who had severe side effects, but not in cells from patients without the side effect. When researchers restored stability in the mice's regulatory T cells, the side effects became much less severe, pointing to this fragility as a major cause.
Researchers restored stability three ways: by blocking a specific signaling protein on the regulatory T cells, by switching mice to a high-fiber diet, or by giving them metabolite supplements.
Gut microbiome transfers show diet shapes severity of immunotherapy side effects
Mice on the Western-style diet also developed gut bacteria changes similar to those seen in people with immune-related inflammation. Transferring gut bacteria from Western diet–fed mice into mice on a regular, high-fiber diet caused gut inflammation in the recipients.
Transferring gut bacteria from male mice—which were less likely to develop severe side effects—into female mice reduced the severity of their inflammation, suggesting gut bacteria composition itself affects outcomes. Transferring gut bacteria from patients eating a Western-style diet into germ-free mice increased the severity of the side effects, further showing that diet and gut bacteria drive the problem.
New targeted therapies could let more patients stay on cancer treatment
The mouse model will now serve as a tool for researchers studying why some patients develop severe side effects and for identifying markers that could predict who is most at risk. Future work will explore drug targets that block the side effect in specific tissues without weakening the cancer-fighting effects of immunotherapy. Metabolite supplementation is also being explored as a way to reduce risk without altering the gut microbiome itself.
"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 said.
Frequently Asked Questions
Q: What causes immune-related adverse events, serious side effects from cancer immunotherapy?
A: Researchers found that unstable regulatory T cells, immune cells that normally prevent excess inflammation, are a major driver. Diet and gut bacteria composition influence cell stability and how severe the side effects are.
Q: Is there an approved treatment for immune-related adverse events?
A: No. The study notes there are currently no treatments approved by the U.S. Food and Drug Administration specifically for this immunotherapy side effect, which affects 20% to 40% of patients, depending on the drug used.
Q: Can diet affect how severe immunotherapy side effects become?
A: In mice, a Western-style diet low in fiber and high in fat and processed carbohydrates worsened the side effects, while switching to a high-fiber diet helped restore immune cell stability and reduce severity.
Additional Resources
- Lifestyle-induced regulatory T cell fragility primes adverse events after immune checkpoint blockade | Cell
- Study identifies key drivers of microbiome-linked cancer immunotherapy side effect | EurekAlert!
- Microbiota-specific T follicular helper cells drive tertiary lymphoid structures and anti-tumor immunity against colorectal cancer | Immunity
- Trust Your Gut: Harnessing the Microbiome to Help the Immune System Fight Cancer | Department of Immunology
- Immunotherapy (Biotherapy) Cancer Treatment | UPMC
Authors: Dipyaman Patra, Ph.D., Katelyn Wolfgang, Chenxian Ye, Lora Rigatti, V.M.D., Kelsey Ertwine, Kristin M. Morder, Jessica Jana, Ishita Baral, Ph.D., Drew Hurd, Kaitlin Bossong, Steven Mullett, Yingtong Dou, Stacy Gelhaus, Ph.D., Dario Vignali, Ph.D., Diwakar Davar, M.D., Anthony Cillo, Ph.D., and Greg Delgoffe, Ph.D., all of Pitt, UPMC Hillman Cancer Center or both.
Funding and Disclosures: This research received support from the National Institutes of Health (DP2AI177967, S10OD023402, S10OD032141, R35 CA263850, S10 OD032265), Damon Runyon Cancer Research Foundation, Gateway Foundation for Cancer Research (G-22-800), Cancer Research Institute Lloyd J. Old STAR Award (CRI3447), Sy Holzer Endowed Immunotherapy Fund, The Pittsburgh Foundation (MR2023-134140), National Institute of Allergy & Infectious Diseases (R01AI171483, R01AI166598), National Cancer Institute (P30CA047904, R01CA277473, P50CA121973, P50CA097190), and UPMC Hillman Cancer Center Skin Cancer and Head and Neck Cancer SPOREs.
