Severe COVID and Flu Leave the Lungs Primed for Cancer, but Vaccines Prevent It

University of Virginia Health System

A bad case of COVID or flu does not just damage the lungs in the short term. According to a study published in Cell by researchers at UVA Health, severe respiratory infections can reprogram the lung's immune environment in ways that promote cancer growth months or even years later. The encouraging counterpoint: vaccination appears to prevent those harmful changes.

The immune system turns traitor

The research team, led by immunologist Jie Sun at UVA's Beirne B. Carter Center for Immunology Research, found that serious viral lung infections had dramatic effects on two types of immune cells that are supposed to protect the lungs: neutrophils and macrophages. Rather than maintaining their surveillance role, these cells were "reprogrammed" by the infection into creating an inflamed, pro-tumor environment where cancer cells could thrive.

The researchers also identified significant changes to the epithelial cells that line the lungs and the air sacs that enable breathing. Together, these cellular changes created what amounts to a long-lasting inflammatory state, a kind of immune scarring that persists well after the infection has cleared and the patient feels recovered.

In mouse models, the consequences were stark. Mice that suffered severe lung infections were both more likely to develop lung cancer and significantly more likely to die from it compared to mice that had not been severely infected.

Human data tells a consistent story

The findings were not limited to mice. When the researchers examined data from human patients, they found a significant association between prior COVID-19 hospitalization and increased lung cancer incidence. The increase was 1.24-fold, meaning hospitalized COVID patients had roughly a 24% higher rate of lung cancer. This held true regardless of smoking status or other health conditions.

The distinction between severe and mild infection proved critical. The increased cancer risk was seen specifically in patients who had been hospitalized for severe COVID-19. Those who had mild cases actually showed a slight decrease in risk. This suggests that the cancer-promoting immune changes are driven by the severity of lung damage and inflammation, not by the virus itself.

Jeffrey Sturek, a UVA physician-scientist and collaborator on the project, drew a direct parallel to how clinicians already think about smoking. Patients with significant smoking histories are recommended for routine screening CT scans to catch lung cancer early. The results of this study suggest that severe respiratory viral infection may deserve similar consideration as a risk factor warranting enhanced monitoring.

Vaccination blocks the harmful changes

In the mouse models, prior vaccination prevented the cancer-promoting lung changes. Vaccines train the immune system to fight infections more effectively, reducing the severity of illness. Because the immune reprogramming that drives cancer risk appears to be a consequence of severe infection specifically, preventing severe disease through vaccination also prevents the downstream cancer risk.

Sun framed this as evidence that vaccines do not just prevent acute hospitalization. They may also reduce the long-term fallout of severe infection, including the kind of immune scarring that elevates cancer risk. This adds another dimension to the benefit calculation for respiratory vaccines, particularly for COVID-19 and influenza.

Tens of millions at potential risk

The researchers note that tens of millions of people globally experienced severe COVID-19 during the pandemic, and many continue to deal with long-term pulmonary effects. If the association between severe infection and cancer risk holds across larger population studies, the implications for surveillance and prevention are substantial.

The team is working to develop methods to identify which patients are at highest risk for infection-related lung cancer, with the goal of enabling earlier detection and targeted prevention strategies. Understanding the specific biological pathways that connect infection to cancer promotion could also lead to therapeutic interventions that reverse the immune reprogramming before cancer develops.

What remains uncertain

The mouse and human components of this study address complementary questions but have different limitations. The mouse experiments demonstrate a biological mechanism but use animal models that do not perfectly replicate human lung cancer development. The human data establishes an epidemiological association but cannot prove causation. Patients hospitalized for COVID-19 may differ from non-hospitalized patients in ways that independently affect cancer risk.

The 1.24-fold increase in lung cancer incidence, while statistically significant, is modest in absolute terms. Translating this into individual risk is difficult without knowing the baseline lung cancer rate in the specific population studied. The latency period between infection and cancer development also remains unclear. The study suggests the risk may persist for years, but exactly how long and whether it eventually resolves is not yet known.

Prospective studies that follow large cohorts of severe respiratory infection survivors over many years will be needed to confirm the association, quantify the absolute risk, and determine whether screening interventions are cost-effective. For now, the biological mechanism identified in mice provides a plausible explanation for the epidemiological finding, and the protective effect of vaccination offers a practical reason for optimism.