Exercise Reverses Obesity-Driven Immune Dysfunction in Lung Cancer: New Insights for Therapy and Prevention

Highlight

• Obesity promotes immune dysfunction in the lung and tumor microenvironment, favoring lung cancer progression by suppressing cytotoxic T-cell function and expanding immunosuppressive populations.
• Voluntary exercise in obese mice reduces the expansion of regulatory T cells (Tregs) and suppressive myeloid cells, while restoring CD8+ T-cell function in both tumor and lung tissue, resulting in delayed tumor growth.
• Transcriptomic analyses reveal exercise induces favorable alterations in vascular and metabolic gene expression profiles in obese mice’s tumors.
• Human bronchoalveolar lavage samples demonstrate that physical activity correlates with reduced PD-1+ Tregs and suppressive myeloid cells, even in adipose-rich individuals, supporting translational relevance.

Study Background

Obesity is a well-recognized risk factor for various cancers, including non-small cell lung cancer (NSCLC). It contributes to a pro-tumorigenic microenvironment through chronic inflammation and immune dysregulation. Specifically, obesity diminishes cytotoxic T-cell responses critical for tumor clearance and promotes expansion of suppressor immune cells such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). This immune suppression not only affects established tumors but also the lung microenvironment where primary and metastatic tumors develop. Exercise is known to improve metabolic health and reduce systemic inflammation. However, whether it can reverse adiposity-driven immune dysfunction in the lung and tumor microenvironment to enhance lung cancer therapy and interception remains insufficiently understood.

Study Design

This study employed an integrative approach using murine models and human samples. Obese and lean mice were implanted with Lewis lung carcinoma cells and assigned to sedentary conditions or provided with voluntary access to running wheels. Tumors and infiltrating immune cells were analyzed through RNA sequencing and flow cytometry to evaluate exercise-induced immune modulation. To assess baseline lung immune profiles, tumor-naïve obese and lean mice were evaluated with and without exercise exposure. Additionally, bronchoalveolar lavage (BAL) fluid from 73 human subjects was examined, stratified by total fat area and physical activity levels with multivariable adjustments to control for confounders.

Key Findings

The pivotal findings demonstrated that in obese mice, voluntary exercise substantially mitigated adiposity-associated immunosuppression. Specifically, exercise reduced the proliferation of Tregs and potentially suppressive myeloid populations within both the tumor and lung microenvironments. Correspondingly, CD8+ T-cell effector deficits commonly observed in obesity were alleviated, restoring their antitumor functionality. These immunological changes were accompanied by significant delays in tumor growth exclusively in obese mice, whereas lean mice exhibited minimal response to exercise in this context.

Transcriptomic analysis of tumors from exercised obese mice revealed extensive modulation in vascular and metabolic gene pathways, providing a mechanistic underpinning for improved immune function and tumor control. The exercise-induced shift suggests enhanced tissue perfusion and metabolic reprogramming conducive to effective immune surveillance.

Parallel human studies strengthened translational relevance, showing that higher physical activity was linked to reduced PD-1-expressing regulatory T cells and suppressive myeloid cells in BAL samples from individuals with higher adiposity. This suggests exercise-mediated immune normalization in human lungs, analogous to murine findings.

Expert Commentary

This study fills a critical gap by demonstrating the immune-modulatory benefits of exercise in obesity-related lung cancer. The findings underscore the interplay between metabolic health, immune regulation, and tumor progression. While previous research has established systemic anti-inflammatory effects of exercise, this study provides detailed insights into local immune microenvironments within lung tumors and surrounding tissue.

Mechanistically, reversing obesity-induced immune suppression through lifestyle interventions like exercise can potentiate responses to both lung cancer interception strategies and immunotherapies. The observed transcriptomic shifts in vascular and metabolic pathways align with growing evidence linking tumor vasculature normalization and metabolic adaptations to improved antitumor immunity.

Limitations include the reliance on a single tumor model and voluntary exercise modality, which might not capture the spectrum of clinical exercise interventions. Further clinical trials are warranted to determine optimal exercise prescriptions and their integration with lung cancer treatment regimens. Additionally, long-term effects and the impact on patient-centered outcomes such as survival remain to be elucidated.

Conclusion

This translational study establishes that exercise can counteract adiposity-induced immune dysfunction in NSCLC and non-tumor lung environments, restoring effective antitumor immune responses and delaying tumor growth in obese hosts. The corroboration of murine and human data provides compelling rationale for integrating structured physical activity into lung cancer prevention and treatment paradigms, particularly for patients with obesity. By modulating immune checkpoints such as PD-1 expressing Tregs and suppressive myeloid cells, exercise emerges as a promising complementary approach to enhance lung cancer interception and therapeutic efficacy.

Future research should focus on defining exercise parameters (intensity, duration, timing) and evaluating synergistic effects with established cancer immunotherapies to fully leverage its clinical potential in improving lung cancer outcomes.

Reference

Smith R Jr, Erickson K, Washington D, Zollo R, Kalvapudi S, Vedire Y, Petrucci C, Rr V, Hsiao HH, Rosario S, Barbi J, Yendamuri S, Ray A. Exercise Modulates Adiposity-induced Immune Dysfunction in NSCLC and Non-tumor-Bearing Lungs: Implications for Lung Cancer Therapy and Interception. Ann Surg. 2026 Aug 6. doi: 10.1097/SLA.0000000000007151. Epub ahead of print. PMID: 42557599.