Multiple observers have noted an apparent association between severe respiratory infection from SARS-CoV-2, influenza, and other viral pathogens and subsequent lung cancer risk. A combination of human and animal data suggests that severe viral respiratory infection can induce inflammatory and epigenetic changes that reprogram the lung into a pro-tumor environment that recruits tumor-enhancing neutrophils and promotes immunosuppression.
“Viral pneumonia epigenetically imprints a pro-tumor lung environment,” said Jie Sun, PhD, Harrison Professor of Medicine/Infectious Disease Division and Co-Director of the Beirne B. Carter Center for Immunology Research at the University of Virginia School of Medicine. “We see a causal link between viral pneumonia and tumorigenesis and cancer growth in the lung. Severe respiratory viral infections can lead to long-term inflammation even after the virus is cleared. Viral pneumonia can set the stage for increased lung cancer risk and lung cancer development. Reducing severe pneumonia with vaccines may reduce lung cancer risk.”
Dr. Sun is the lead author of a recent paper in Cell that expands the evidence base in this area of research.1 The retrospective analyses found that severe COVID-19 was associated with a 1.24 hazard ratio for subsequent lung cancer after adjustment for gender, age, and smoking status. Severe COVID-19 was associated with increased lung cancer risk independent of other conditions. Severe influenza infection has also been associated with increased lung cancer risk, suggesting that viral pneumonia may provide a common pathway to increased lung cancer risk.
“The idea of viruses mediating malignancy is not, in and of itself, new,” said Ryan Maves, MD, FCCP, Professor of Medicine and Anesthesiology at Wake Forest University School of Medicine. “The classical case is cervical cancer and human papilloma virus [HPV]. HPV-associated malignancy, including cervical cancer, head and neck cancer, penile cancer, and anal cancer, is well-described.”
Dr. Sun and colleagues used murine models to tease out the inflammatory and immunological changes associated with severe COVID-19 and influenza infection. Viral pneumonia primed the lung for tumorigenesis and cancer progression. Bacterial pneumonia showed a numerical trend for increased tumor growth but not tumorigenesis, Dr. Sun said, and the increase in tumor progression was not statistically significant.
Single-cell studies showed that respiratory viral infections reprogrammed lung epithelial cells toward more proliferative states, where granulocyte colony-stimulating factor, interleukin-6, and a variety of chemokines are upregulated to promote neutrophil development, recruitment, and survival. The lung microenvironment becomes enriched with tumor-associated neutrophils (TANs), which promote immunosuppression, glycolysis, hypoxia, and angiogenesis, thereby driving tumor growth. These same TANs correlate with reduced survival in human lung adenocarcinoma.
“We still see a 24% increase in lung cancer risk in people who were hospitalized for COVID, but what we have looked at is still relatively short-term,” Dr. Sun said. “We don’t know yet what the longer-term impact of viral pneumonia on the risk of lung cancer may be. Now that we know viral pneumonia likely increases lung cancer risk, people have another very good reason to be vaccinated against influenza, RSV, and COVID to prevent future severe pneumonia.”
Dr. Maves said that while the mechanisms linking viral pneumonia and lung cancer risk are more hypothesis-generating than confirmed at this point, the data all point to potential benefits from increasing vaccine uptake.
“This lends more weight to the need to protect people against respiratory viruses as part of lung cancer prevention,” he said. “Just like the HPV vaccine prevents cervical cancer, we can make a very plausible case that getting vaccinated against flu, COVID-19, and RSV reduces your risk of lung cancer.”
References
1. Qian W, Wei X, Barros AJ, et al. Respiratory viral infections prime accelerated lung cancer growth. Preprint. bioRxiv. 2025;2025.09.02.672566. doi:10.1101/2025.09.02.672566
