Researchers at the University of Michigan Health Rogel Cancer Center have revealed new insights into why smoking dramatically increases the risk and severity of pancreatic cancer. The study, published on 4 September 2025 in the journal Cancer Discovery, explored and provided details on how cigarette-related chemicals alter immune cell behavior and promote aggressive tumor growth in both animal models and human patients.
Interleukin-22 and Treg Cells: University of Michigan Study Uncovered How Smoking Triggers an Immune Response that Drives Faster and Deadlier Pancreatic Cancer
Background and Research Overview
Pancreatic cancer is one of the deadliest types of cancer. Most patients receive diagnoses at advanced cancer stages. Previous research has shown that smokers face a markedly higher risk of developing the disease. However, the exact biological explanation for this connection has remained unclear. A team of researchers sought to address this crucial knowledge gap.
The investigation was headed by physician and Rogel and Blondy Center for Pancreatic Cancer co-director Timothy L. Frankel, M.D. His team pursued the study to explain why pancreatic cancer progresses more aggressively in smokers and to determine potential intervention points for therapeutic strategies and clinical management.
Researchers used mouse models implanted with pancreatic tumors. They exposed these mice to a carcinogen found in cigarette smoke. Both the size and spread of tumors, as well as immune activity, were monitored. Parallel experiments were conducted on immunodeficient mice to determine the importance of the immune system in pancreatic cancer progression.
Discovering the Smoking-Cancer Mechanism
Findings showed that cigarette-related chemical exposure caused dramatic tumor enlargement and widespread metastasis in immunocompetent mice. However, immune-deficient mice did not display similar outcomes, proving that the immune system mediates the tumor-promoting effect. Laboratory analysis focused on specific immune activities.
Researchers discovered a clear mechanism through which smoking-related chemicals promote the progression of pancreatic cancer. The evidence connected the release of the specific cytokine called interleukin-22 and the activity of a unique subset of T-regulatory cells with tumor acceleration. The following are the principal findings reported in the investigation:
• Accelerated Tumor Growth: Cigarette-related chemicals enlarged tumors and promoted aggressive metastasis in mouse models. This demonstrated a direct connection between chemical exposure and cancer severity.
• Immune Dependence: It is important to note that tumor growth acceleration and disease progression occurred only in immune-competent mice. This highlights the role of immune activity in the harmful impact of smoking.
• Interleukin-22 Cytokine Role: Chemicals in cigarettes stimulate immune receptors and trigger the release of interleukin-22. This cytokine was observed to reshape the tumor environment in favor of cancer growth.
• Super-Suppressive Treg Cells: Researchers identified a subset of T-regulatory cells that both produced interleukin-22 and suppressed anti-tumor immunity. These mechanisms worsened pancreatic cancer progression.
• Reversal By Treg Depletion: Note that depleting these subsets of T-regulatory cells from mice reversed the tumor-promoting effect of cigarette chemicals. This further confirms their critical role in worsening progression.
• Specific Human Confirmation: Smokers with pancreatic cancer had elevated levels of these specialized T-regulatory cells compared with non-smokers. This provides further evidence to support the mouse findings.
• Therapeutic Inhibition: Researchers also discovered that blocking the receptor used by cigarette chemicals reduced tumor size. This presents a possible therapeutic approach to counteract the effects of smoking.
Why These Results Matter
The research provides a biological explanation for why smokers experience worse pancreatic cancer outcomes. By identifying the role of interleukin-22 and super-suppressive T cells, scientists discovered how smoking creates an immune environment that promotes tumor progression, offering valuable insights into treatment and prevention strategies.
New therapeutic opportunities were also identified. Targeting interleukin-22 or depleting harmful T-regulatory cells could restore natural anti-tumor mechanisms. Combining these approaches with existing immunotherapies might overcome the resistance of pancreatic cancer to treatment. This is true for smokers who have an altered and tumor-promoting immune environment.
It is also worth mentioning that the findings underscore the importance of prevention and early detection. Both individuals and current patients with a history of smoking may benefit from closer monitoring, referral to high-risk clinics, and stronger education on early warning signs such as unexplained weight loss, jaundice, and persistent back pain.
FURTHER READING AND REFERENCE
- Griffith, B. D., Kadiyala, P., McGue, J., Sun, L., Kumar, A., Espinoza, C. E., Donahue, K. L., Iyer, M. K., Speyer, C., Nelson, S., Spiteri, A., Elhossiny, A. M., Brown, K., Attebury, H., Bednar, F., Carpenter, E. S., Kryczek, I., Zhang, Y., Zou, W., … Frankel, T. L. 2025. “Aryl Hydrocarbon Receptor Ligands Drive Pancreatic Cancer Initiation and Progression through Pro-Tumorigenic T Cell Polarization.” Cancer Discovery. DOI: 1158/2159-8290.cd-25-0377