Chronic inflammation has long been considered one of the factors contributing to cancer development. This applies to both noninfectious diseases and infections. For example, Helicobacter pylori increases the risk of gastric cancer, while hepatitis B and C viruses are associated with the development of liver cancer. Epidemiological studies have also shown an association between viral pneumonia and an increased incidence of cancer. However, it remained unclear how severe respiratory tract viral infections affect the risk of lung cancer.
In a 2026 study in Cell, Qian and colleagues showed that severe viral pneumonia can alter gene expression in the lungs, creating a favorable environment for tumor growth. An analysis of medical data from 75.9 million people showed that patients who had experienced severe COVID-19 had a 1.24-fold higher risk of developing lung cancer even after accounting for age, sex, and smoking. Mild and moderate forms of the infection, however, were not associated with an increased risk, indicating that the severity of lung injury itself plays an important role.
To establish a causal relationship, the researchers used several mouse models exposed to viruses. Regardless of the model, prior infection with SARS-CoV-2 or influenza A virus increased both tumor number and size and reduced survival.
To investigate the mechanisms underlying tumor progression, the researchers examined how viral infections alter the local lung environment. After severe viral infection, the composition of immune cells in the lungs remained altered for an extended period. Tumor-associated SiglecF^hi neutrophils accumulated in the tissue, while CD8+ T lymphocytes responsible for destroying tumor cells became exhausted. Single-cell hi-C data revealed that neutrophils promoted tumor growth while simultaneously suppressing the antitumor T-cell response.
These changes were associated with epigenetic reprogramming of lung cells. After infection, the activity of the Csf3 gene, which encodes G-CSF, increased in macrophages, epithelial cells, and fibroblasts. As a result, the production of SiglecF^hi neutrophils increased. Blocking the G-CSF receptor reduced the number of SiglecF^hi neutrophils and suppressed tumor growth.
Prevention and Treatment of Lung Tumors Associated with the Consequences of Severe Viral Infections
In preclinical models:
- Combining a CXCR2 inhibitor with PD-L1 blockade simultaneously reduced neutrophil recruitment to the tumor and restored the antitumor activity of CD8+ T lymphocytes. As a result, tumor growth was significantly slowed.
- Vaccination against COVID-19 and influenza completely prevented the increase in tumor growth caused by viral infection. This suggests that the protective effect of vaccination extends beyond preventing acute disease. Vaccination may also prevent remodeling of the lung immune microenvironment, which promotes tumor development. Particular attention should be paid to people who have experienced severe viral infections, especially smokers, because the severity of the infection determines the long-term risk of developing lung cancer.
Reference
Epigenetic remodeling after viral pneumonia accelerates lung tumorigenesis
