Obesity Weakens Cancer Immunity. Can GLP-1 Drugs Turn It Back On?

For decades, doctors have known that obesity raises the risk of breast cancer. What’s been harder to explain is why. How does carrying extra weight change the body’s inner workings, and could those changes affect how well cancer treatments work?  

Duke University School of Medicine scientist Erika J. Crosby, PhD, thinks the answer may lie in the immune system itself.  

Her lab is researching how extra weight can dull the body’s cancer defenses — and how blockbuster GLP-1 drugs like Ozempic might help reset them.  

In recent experiments, Crosby’s team tested a vaccine targeting the HER2 protein, a molecule found on the surface of certain aggressive breast cancers. The vaccine worked flawlessly in lean mice, triggering an immune response that blocked tumor growth. In obese mice, the same vaccine, given in the same dose, offered almost no protection at all.  

“It was a significant loss of efficacy,” said Crosby, a cancer immunologist at the Duke Cancer Institute. “The immune system just didn’t seem to recognize the threat in the same way.”  

The findings reinforced something oncologists have long suspected: obesity doesn’t just increase the risk of getting cancer. It may also weaken the immune system, making it harder to detect cancer and reducing the effectiveness of cancer vaccines and immunotherapy.  

A sharper risk after menopause  

Those risks are especially concerning for women after menopause. Once estrogen production in ovaries slows, fat tissue becomes the body’s main source of the hormone, and estrogen can help certain breast cancers grow.  

Postmenopausal women with obesity, especially those with a body mass index above 35, face up to a 60% higher risk of developing invasive breast cancer compared with women at a healthy weight, a 2015 study shows.  

But what’s emerging from Crosby’s work is a more complicated picture. The connection to estrogen is one factor. Fat tissue can also trigger inflammation that acts as a slow simmer that exhausts the immune system. It seems to reprogram how the immune system interacts with cancer — how it sees it, responds to it, or sometimes, fails to.  

Crosby’s team is now asking a new question: if obesity disrupts the immune system, could weight loss help fix it? 

To find out her lab compared three methods — diet changes, bariatric surgery, and GLP-1 receptor agonists, the class of drugs behind brand names like Ozempic and Mounjaro. Originally developed for diabetes, the medications help regulate blood sugar and suppress appetite, leading to significant weight loss.  

Today, one in five women ages 50 to 64 in the United States use GLP-1 drugs, the same age group most at risk for breast cancer. 

When Crosby’s team tested GLP-1 drugs in obese mice, they developed tumors more slowly and their overall cancer risk dropped sharply — so sharply, in fact, that it nearly matched that of the lean mice. The protective effect occurred even when the animals continued eating a high-fat diet.  

“Weight loss induced by these drugs can completely reverse and in some cases more than reverse the increased tumor risk of developing a breast tumor that we see in obesity,” said Crosby, an assistant professor in the Department of Surgery and the Department of Integrative Immunobiology.   

Researchers used mouse models that let them focus on and study specific biological processes. 

The results suggest that these drugs might be doing something beyond lowering weight. GLP-1 medications influence metabolism throughout the body and that could ripple into how cells — including immune and cancer cells — use energy.  

It’s possible they’re not just resetting metabolism but also recalibrating the immune system, helping it to recognize cancer again as a threat.  

Understanding the microenvironment  

Across cancer research, obesity is often viewed as an epidemiological issue — a statistical link between weight and disease. Crosby’s work at Duke is pushing the field toward understanding it as a biological mechanism.  

“There are 13 cancers tied to obesity,” she points out. “We know the associations, but we don’t yet understand exactly why it happens or how to reverse it.”  

"A more holistic view of the microenvironment, including obesity, could have an important impact on treatment decisions and success."

 - Erika Crosby, PhD, cancer immunologist

She believes that the immune dysfunction seen in obesity could be one reason cancers develop faster and respond differently to treatment.  

"The field of immunology has done a lot of work on chronic infections and how they alter immune function but viewing something like obesity as a chronic inflammatory condition and understanding how it changes tumors is a part of the story that's need more exploration," she said.

Breast tissue and screening 

Crosby and her colleagues are already working on follow-up research. With radiologist Lars Grimm, MD, she is studying how weight loss affects breast tissue density, a trait that can make tumors harder to detect on mammograms. Under new federal rules, women must be notified if they have dense breasts, prompting conversations about supplemental screening. 

“Breast cancer is such a multi-disciplinary field, and I am very excited to include imaging at an early stage in this line of investigation,” said Grimm. 

Meanwhile, Crosby is collaborating with Jeffrey Marks, PhD, a Duke cancer researcher and professor of experimental surgery, to analyze breast tumors among women who are taking GLP-1 drugs when diagnosed, searching for biological differences that might hint at direct drug effects.  

With Duke endocrinologist Afreen Shariff, MBBS, a member of the Duke Cancer Institute Center for Onco-Primary Care, she’s studying how GLP-1 medications might fit into treatment plans for cancer survivors — a group for whom obesity can raise the risk of cancer coming back. 

And there’s another population Crosby is especially interested in:  women with ductal carcinoma in situ (DCIS), a non-invasive condition that can progress to breast cancer. She believes GLP-1 drugs could one day become part of a preventive strategy for such patients, potentially lowering their odds of developing invasive disease. 

Next frontier in personalized medicine 

For all its promise, the research is still in its early stages. The biology of metabolism, immunity, and cancer is immensely complex, and animal findings don’t always translate neatly to humans.  

Still, Crosby sees the potential for a new kind of cancer prevention strategy — one that focuses not just on tumors themselves, but on the environment that allows them to grow and how to change it. 

“I think of this as really the next step in personalized medicine,” Crosby said. “There’s so much we want to explore. The challenge is distilling our questions down into the few that we can answer now and then expanding as our pipelines and the interest of investigators grow.”  

Carolyn Dean is a communications strategist at the Duke Cancer Institute.  

Eamon Queeney is assistant director of multimedia and creative in the Office of Strategic Communications at the Duke University School of Medicine.