Severe COVID and influenza infections can “reprogram” cells in the lungs, priming the environment for cancer growth.
During respiratory virus infection, interactions between the pathogen and the host’s immune response can result in tissue damage and inflammation that persist for years after viral clearance. Severe inflammation can lead to pneumonia or respiratory distress, and it can leave scarring, also known as fibrosis.
“Previously, we observed that acute influenza infection could induce persistent inflammation and fibrosis,” Dr. Jie Sun, professor of medicine at the University of Virginia and corresponding author of the new study, told Technology Networks.
Inflammation and fibrosis are risk factors for lung cancer, leading Sun to investigate whether influenza infection facilitates primary lung cancer development. When the COVID-19 pandemic hit, Sun expanded his research to examine lung cancer risk following COVID-19 infection.
“The COVID-19 pandemic provided us with a unique context to study this [infection and lung cancer risk] because so many people got so sick with the same virus at the same time,” he said.
Viral infection increases lung cancer risk
The researchers conducted a retrospective cohort study using the Epic Cosmos database, identifying 75.9 million adults who had mild-to-moderate COVID-19, severe COVID-19 (requiring hospitalization), or were uninfected during 2020–2021.
Patients who had severe COVID-19 had a modest increase in overall cancer incidence and a higher risk of lung cancer, based on cancer diagnosis data from 2022 onwards. After adjustment for gender, age, and smoking status, severe COVID-19 infection was associated with a 1.24-fold increase in cancer risk.
However, with this retrospective analysis, there is the possibility that some individuals who were hospitalized with COVID-19 had pre-malignant lesions that contributed to severe infection and later cancer growth.
Sun and his team used animal models to investigate the mechanisms behind how prior respiratory infection increases lung cancer risk.
Mice were infected with SARS-CoV-2, influenza, or a control, then, three weeks after infection, cancer cells were introduced to the lungs. The researchers monitored tumor burden and survival. They confirmed that prior infection with SARS-CoV-2 or influenza enhances tumor growth and significantly reduces survival.
Further experiments illustrated that prior viral pneumonia also promotes cancer development, indicating that viral infections prime the lungs for tumorigenesis and cancer progression.
Forming a tumor-supportive environment
Single-cell sequencing of lung cells 6 and 12 weeks post-tumor induction revealed that prior infection reprograms neutrophils and macrophages to display higher pro-tumor signatures. CD8+ T cells also exhibited higher exhaustion signatures in virus-experienced tumors.
Epigenetic reprogramming of these immune cells—caused by viral infection—increases pro-tumor inflammatory responses when oncogenes initiate tumor development, creating an environment in which cancer cells can thrive.
Once the cancer has established, immune cell reprogramming further influences the tumor microenvironment, which then shapes cancer growth.
“Epithelial cells were also epigenetically reprogrammed by prior severe infection and produced more pro-tumor inflammatory cytokines upon tumor initiation/encounter, contributing to a cancer-permissive environment,” Sun explained.
Vaccination mitigates against cancer-promoting changes
Vaccination doesn’t just prevent hospitalization after viral infection; it may also reduce the long-term impacts of infection, the researchers report.
“We found that the cancer promotion effects require prior severe infection in animal models,” said Sun. “In mice, we found that prior vaccination prevents severe disease development, thereby dampening the pro-tumor effects of infection.”
As vaccination in humans also helps prevent severe infection by “training” the immune system to respond more effectively to pathogens, it may also mitigate the pro-tumor effects of viral infections. Sun cautions that direct evidence in humans is needed to confirm this hypothesis.
Implications for clinical care
As the tissue damage and inflammation from viral infection can persist for years, these findings indicate that lung cancer risk is also increased from months to years after apparent recovery from viral infection.
Considering the tens of millions of people worldwide who are experiencing long COVID, this research carries significant implications for clinical care and cancer screening.
“We believe that individuals at high risk of lung cancer, such as smokers, may need to pay greater attention to early detection of lung cancer following a prior severe infection,” said Sun.
Furthermore, the insights into how immune and epithelial cell reprogramming support cancer growth could spur further research into biomarkers and therapeutics.
“There is a pressing need to identify molecular signatures or biomarkers that can better predict lung cancer risk in patients, as well as to develop strategies that target virus-induced pro-cancer niches for lung cancer treatment,” Sun concluded.
Reference: Qian W, Wei X, Barros AJ, et al. Respiratory viral infections prime accelerated lung cancer growth. Cell. 2026. doi: 10.1016/j.cell.2026.02.013
About the interviewee:
Dr. Jie Sun is the Harrison Professor of Medicine/ID and co-director of the Carter Immunology Center. He was a faculty member at Indiana University and the Mayo Clinic before joining the University of Virginia in 2022. His lab has been studying the immune mechanisms underlying mucosal protection, lung recovery, and chronic sequelae after respiratory viral infections, including influenza and COVID-19. His lab further explores immune cell function in cancer and tissue aging, seeking ways to boost anti-tumor response and rejuvenate older populations by targeting the immune system.