A new study explains how cigarette smoke may worsen pancreatic cancer by reprogramming the immune system to favor tumor growth and spread. While smoking has long been linked to pancreatic cancer, the exact mechanism was unclear. The University of Michigan team reports that chemicals in smoke called aryl hydrocarbon receptor ligands (AhRLs) — including carcinogens like dioxins — activate immune pathways that suppress anti-tumor responses. The full results were published September 4 in Cancer Discovery.
Methods and main findings
– Researchers used lab experiments, mouse models, and human pancreas tissue to study the effects of cigarette smoke–related AhR ligands. Mice received cigarette smoke extract or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent AhR ligand, and pancreatic cancer cells were implanted into their pancreases to monitor tumor behavior.
– Tumor growth accelerated in mice exposed to cigarette smoke or TCDD, but only when their immune system was intact, showing the effect is immune-mediated rather than a direct toxin-driven increase in tumor cell proliferation.
– The critical mechanism involves activation of the aryl hydrocarbon receptor (AhR) on CD4+ T cells. Once activated, these cells produced more IL-22 and drove an increase in regulatory T cells (Tregs).
– Tregs suppress immune activity and, in this case, limited CD8+ T cells — the immune cells that normally attack cancer — allowing tumors to grow and spread.
– Exposure to TCDD also promoted early precancerous changes in the pancreas, suggesting AhR ligands may contribute to both cancer initiation and progression.
– Human pancreas samples mirrored mouse results: smokers showed greater AhR pathway activation and higher numbers of Tregs in pancreatic tumors. The number of Tregs correlated with patients’ lifetime smoking exposure.
Implications and cautions
– The authors suggest blocking AhR activation or reducing Treg-mediated suppression could be therapeutic strategies to restore anti-tumor immunity, particularly for smokers. Because AhR ligands are found in other pollutants and industrial chemicals, the findings may have broader public-health relevance.
– Experts urge caution. Asfar Azmi, PhD, director of the Pancreatic Cancer Research Initiative at the Barbara Ann Karmanos Cancer Institute, noted much of the evidence is from lab and animal studies plus human tissue analyses, so the work shows a plausible mechanism linking smoking and pancreatic cancer but does not prove that every smoker will develop the disease or that blocking this pathway will prevent it. More clinical research is needed before changing treatment practices.
Public-health context and advice
– Pancreatic cancer is highly lethal, with a five-year survival rate around 13%. In 2025 it’s estimated that more than 67,000 Americans will be diagnosed and nearly 52,000 will die from the disease.
– Najeeb al Hallak, MD, MS, a medical oncologist at the Barbara Ann Karmanos Cancer Institute, said the study reinforces that quitting smoking is one of the best steps to lower pancreatic cancer risk. Smoking cessation also reduces the risk of many other cancers and cardiovascular and lung diseases.
– al Hallak recommends that heavy smokers discuss pancreatic cancer risk and possible monitoring with their doctors. For quitting, clinicians can advise nicotine replacement (patches, gum, lozenges) or medications to reduce cravings. Counseling, support groups, and quitlines (for example, 1-800-QUIT-NOW) increase the chances of success. He emphasized planning for triggers, creating healthier routines, and not being discouraged by relapses — many people require multiple attempts before quitting permanently.
Bottom line
The study identifies a specific immune pathway by which cigarette smoke–related chemicals may promote pancreatic cancer initiation and progression: activation of AhR on CD4+ T cells leading to IL-22 production and expansion of Tregs that suppress anti-tumor CD8+ activity. This provides a potential target for future therapies and adds another strong reason to avoid or quit smoking.
