Challenging “Obesity Paradox,” Obesity-Driven Immune Suppression May Increase NSCLC Risk

Obesity may promote the development of non–small cell lung cancer (NSCLC) by suppressing the immune system’s ability to eliminate emerging tumors, according to new findings published in the Journal of Thoracic Oncology.¹ Investigators from Roswell Park Comprehensive Cancer Center found that excess abdominal fat was associated with increased lung cancer risk in individuals with a history of smoking, challenging the long-debated "obesity paradox," which suggested that higher body mass index (BMI) may protect against lung cancer.¹

Abdominal Fat Linked to Increased Lung Cancer Risk

Although obesity has long been recognized as a risk factor for multiple malignancies, its relationship with lung cancer has remained controversial. Previous epidemiologic studies that use BMI as a measure of obesity reported an inverse association between higher BMI and lung cancer incidence, raising questions about whether obesity might confer a protective effect.¹ However, BMI does not distinguish between fat and lean body mass or account for fat distribution, potentially limiting its accuracy as a marker of metabolic risk.²

To better evaluate obesity-related risk, investigators conducted a case-control study involving 1170 current or former smokers who were at elevated risk for lung cancer. The analysis included 594 patients with stage 1 or 2 NSCLC who underwent surgical treatment between 2009 and 2020, and 576 individuals enrolled in a lung cancer screening program between 2015 and 2022. Rather than relying on BMI, researchers measured total abdominal fat area (TFA) using CT imaging, providing a more physiologically meaningful assessment of excess adiposity.¹

Higher TFA was independently associated with an increased likelihood of developing lung cancer in both univariate and multivariable analyses, suggesting that excess abdominal fat—not simply body weight—may be an important contributor to lung carcinogenesis.¹

Immune Dysfunction Identified in the Airways

To better understand the underlying biology, investigators evaluated airway gene expression and immune cell populations in both patient samples and preclinical models. Individuals with higher TFA demonstrated gene expression patterns consistent with suppressed immune activity within the airways.¹

Further analyses revealed increased numbers of activated regulatory T cells (Tregs), which suppress immune responses, along with deficiencies in tumor-fighting effector T cells. Obese mouse models similarly demonstrated an accumulation of immunosuppressive myeloid cells and functional Tregs before and during tumor development, creating an environment that allowed lung tumors to develop more rapidly than in lean controls. Functional depletion experiments suggested that obesity-enhanced Tregs directly contributed to accelerated tumor growth, while bronchoalveolar lavage samples from patients also supported evidence of impaired immune surveillance in individuals with excess abdominal fat.¹

According to Sai Yendamuri, MD, MBA, FACS, senior study author, the findings provide strong evidence that obesity actively contributes to lung cancer development by weakening immune defenses before tumors are clinically detectable.^1,3 Senior author Joseph Barbi, PhD, added that obesity appears to impair the lung's immune surveillance during the earliest stages of carcinogenesis.³

Clinical Implications for Pharmacists

About two-thirds of US adults have a BMI greater than 25, and obesity is already recognized as a risk factor for at least 13 cancer types.⁴ These findings suggest that body composition—particularly visceral adiposity—may warrant greater consideration during lung cancer risk assessment among current and former smokers.¹

For pharmacists caring for patients with obesity or smoking histories, the study reinforces the importance of counseling on smoking cessation, weight management, and adherence to recommended lung cancer screening guidelines for eligible individuals.⁵ As researchers continue investigating obesity-driven immune dysfunction, future preventive strategies targeting immune suppression within the lung may help reduce early-stage NSCLC development in high-risk populations.¹

REFERENCES

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

2. Adult BMI Categories. CDC. March 19, 2024. Accessed July 8, 2026. https://www.cdc.gov/bmi/adult-calculator/bmi-categories.html

3. Roswell Park Comprehensive Cancer Center. Obesity Promotes Lung Cancer by Suppressing Immune Response, Roswell Park Study Shows. Newswise. July 7, 2026. Accessed July 8, 2026. https://www.newswise.com/articles/obesity-promotes-lung-cancer-by-suppressing-immune-response-roswell-park-study-shows

4. Obesity and Cancer Fact Sheet. National Cancer Institute. Updated January 28, 2025. Accessed July 8, 2026. https://www.cancer.gov/about-cancer/causes-prevention/risk/obesity/obesity-fact-sheet

5. US Preventive Services Task Force, Krist AH, Davidson KW, et al. Screening for Lung Cancer: US Preventive Services Task Force Recommendation Statement. JAMA. 2021;325(10):962-970. doi:10.1001/jama.2021.1117