Beyond BMI: Unraveling the Obesity Paradox in Lung Cancer

Obesity’s relationship with lung cancer has been difficult to define, with some risk prediction models suggesting that a higher body mass index (BMI) may be protective against the disease. New research suggests that how obesity is measured may help explain this paradox, while offering insight into the biological mechanisms linking excess body fat to lung cancer development.

Published in the Journal of Thoracic Oncology, the study, led by investigators at Roswell Park Comprehensive Cancer Center, found that obesity was associated with increased lung carcinogenesis in preclinical models, potentially through heightened regulatory T-cell activity.¹ Human patient data supported these findings, suggesting that body composition and obesity-related immune changes may be important considerations in understanding lung cancer risk.

In an interview with Targeted Onc™, Sai Yendamuri, MD, MBA, FACS, chief strategy officer, professor and chair emeritus of thoracic surgery at Roswell Park Comprehensive Cancer Center, and study senior author, commented on how these findings challenge conventional approaches to measuring obesity, the potential for weight management interventions to reduce lung cancer risk, and how clinicians can counsel patients on healthy weight loss.

Targeted Onc: What do you think has contributed to the conflicting evidence around obesity and lung cancer risk?

Sai Yendamuri, MD, MBA, FACS: The problem with obesity measurements in the past, and I would say largely even now, is the use of BMI as a measure of obesity, because BMI doesn't take body composition into account. You could have a bodybuilder who has a very high BMI, but it doesn't mean they're obese; if anything, they're amongst the leanest of human beings. That's been the problem, and so more and more experts in obesity are moving away from using BMI. I think we in the cancer research world, looking at obesity's impact on cancer, should also move away from BMI. I think using body composition in some way, shape, or form—the cheapest man's measure of body composition is waist circumference, or waist-hip ratio—gives you a better measure of body composition than BMI does. But of course, now we have CT scans. Every patient with cancer gets a CT scan, so why not just use a CT scan as a measure for body composition? I think that the divergence between BMI and body composition is what we believe explains a lot of the confounding data that we've seen in the past.

How did your study aim to help clarify that relationship?

The background for doing the study is that if you look at most nomograms or prediction algorithms for lung cancer risk, what they found is that BMI as a measure of obesity was actually protective; that is, people with higher BMI had a lower risk [of lung cancer], and this counters everything we know about obesity and cancer. We know that obesity leads to chronic inflammation that promotes cancer. So, we said, let’s test this out. Instead of using BMI, we looked at total fat measured on a CT scan in patients who are at risk for cancer and patients who actually have early-stage lung cancer. What we found is patients who have early-stage lung cancer have a greater proportion of body fat than patients who are just at high risk but who have not developed lung cancer. So then we said, let's go back and model this in mice and see what happens. We took mice that were both lean and mice that were made obese by feeding them a standard high-fat diet, and then we exposed them to a carcinogen.

What were the key mechanistic findings from your study?

The mice that were obese developed cancer much more [frequently] than the mice that were not; the same thing [happened] with genetically modified mouse models as well. When we looked at what is happening to the immune system, what struck us is how regulatory T cells became more active with obesity, and they seem to be the central player in making this happen.

We then [asked], if regulatory T cells are the culprit, is this mechanism operative, even in patients who are obese? It turned out that we had a set of data where patients were undergoing a bronchoscopy for standard of care reasons. We took what we call bronchial lavage samples; we push some fluid into the lungs and get it back, and that sort of gets a biopsy of a normal lung, for lack of a better word. We had immunophenotyped those samples and looked at the immune cell composition…to see what those immune cells were doing. What we found there was exactly what we found in mice: the patients who were obese, and the patients who were obese by visceral fat measurements or by total fat measurements, had a higher activity of regulatory T cells than those patients who were not obese.

So, we looked at observations in human beings and in patients; we then modeled it in mice, trying to understand fundamental mechanisms of what happened in mice and seeing if those mechanisms were operative in human beings. So, it's a bedside-to-bench and back to bedside sort of investigation. Everything that we saw was consistent with what our modeling [showed]; that is, obesity seems to change how regulatory T cells operate and that seems to predispose them to lung cancer carcinogenesis. We think that this is incredibly important because this means that obesity clearly is bad for lung cancer incidence, and now we have a good scientific rationale to target obesity as a lung cancer prevention mechanism.

What additional research is needed to propel such lung cancer prevention efforts?

We've already started doing some research on this. One of the early thoughts that we had—and these are thoughts going back 5 years—[was to] look at metformin, a common drug, to see if it can reverse the bad effects of obesity. We just completed the trial and are analyzing the data. By the end of the year, we should have an idea if in human beings it can reverse what obesity does.

The natural next question everyone has on their mind is, would exercise reverse this? We do find in preclinical experiments that exercise does reverse this. The next question people have is, can glucagon-like peptide-1 [GLP-1] receptor agonists like semaglutide [Ozempic] or tirzepatide [Mounjaro] reverse it? We are pitching a trial [investigating this question] to the NCI to see if we can do that trial. We are excited about the possibility of doing a trial like that because I think that's on everyone's mind. It's on our mind as well, and it's been on our minds for a long time. In animal experiments, it seems to work, but animals are not human beings, and so we have to do this trial in human beings and see if we find the same results.

I would encourage other researchers in other cancer sites, especially those cancer sites that are not considered the typical 13 obesity-related cancers, to do research of this kind in their areas and increase the amount of evidence that supports the fight against obesity in patients with cancer. I'm sure many people already are.

Based on these findings, should clinicians think differently about obesity as a lung cancer risk factor? How should they counsel patients?

With our data—not just with this particular paper, but our data from multiple papers on this topic—I think I'm comfortable saying that community medical oncologists should encourage their patients to lose weight in a healthy way; to lose weight not [by] losing muscle mass, but by losing actual fat mass. I think everything that we generally think is good for good health—exercise, diet, losing visceral fat—are all good for patients with cancer, not just for general health, but also from the point of view of fighting the cancer. Now we have a good scientific basis for that recommendation—what’s there to lose?

REFERENCE

1. Barbi J, Smith RJ, Vedire YR, et al. Obesity Promotes Lung Carcinogenesis Through Airway Immune Dysfunction. J Thorac Oncol. 2026;21(10):104066. doi:10.1016/j.jtho.2026.104066