Breast cancer is the most common malignancy in women and the second leading cause of cancer death in the United States. Following treatment, some cancer cells can persist in a dormant state for years. Over time, these cells can reactivate, leading to metastases – most frequently in the lungs, bones, or liver. Whether these cells remain inactive or begin to proliferate depends on both intrinsic cellular processes and the surrounding tissue environment. One factor that promotes metastasis is inflammation.
Respiratory viral infections – such as influenza and COVID-19 – are associated with lung inflammation, accompanied by elevated inflammatory cytokines, including IL-6 and interferons. This immune activation involves neutrophils, macrophages, and T lymphocytes. Specific inflammatory mechanisms – including IL-6/STAT3 signaling, neutrophils and neutrophil extracellular traps, and CD4–macrophage interactions – may influence metastasis development.
During the first two years of the COVID-19 pandemic, cancer mortality increased, which cannot be explained solely by COVID-19–related deaths or delays in screening and treatment. The University of Colorado team hypothesised that lung viral infections may drive cancer mortality by triggering metastases from dormant cancer cells. They investigated:
- The impact of influenza virus and SARS-CoV-2 infection on metastases in mice with dormant breast cancer.
- Clinical data from cancer survivors with documented SARS-CoV-2 infection, assessing the risk of metastasis and mortality.
Viral Infections Increase the Risk of Activating Dormant Breast Cancer Cells
Respiratory viruses promote the awakening and expansion of previously dormant disseminated cancer cells (DCC) through a two-phase process:
1. IL-6–Mediated Activation
Upon influenza infection, signaling pathways for IFN-α, IFN-γ, TNF, and IL-6–JAK–STAT3 are activated. Lung IL-6 levels rise sharply, with epithelial cells as the primary source. IL-6 directly stimulates the proliferation of HER2-expressing tumor cells – HER2 being a receptor whose overexpression drives cell division and is associated with aggressive breast cancer – and promotes lung metastasis formation.
In mice with dormant breast cancer and IL6 knockout, influenza infection did not increase HER2 cell counts in the lungs – they remained dormant. The absence of IL-6 prevented post-infection metastasis development.
Experiments with a mouse-adapted SARS-CoV-2 strain showed that COVID-19 infection also produced high IL-6 and IFN-α levels, significantly expanding HER2 cell populations in the lungs, with activation and proliferation signatures similar to influenza infection. In IL6 knockout mice, these changes were much less pronounced, and viral replication was unaffected.
2. Immune Evasion Through CD4 Niches
DCC then re-enter dormancy, forming CD4 lymphocyte niches that protect them from CD8-mediated killing. HER2 cells can induce CD4 lymphocytes to acquire a phenotype that suppresses anti-tumor immunity. Depleting CD4 lymphocytes restored CD8 activity and eliminated influenza-activated DCC.
COVID-19 and Cancer Progression
UK Biobank analysis showed that in cancer survivors, a positive SARS-CoV-2 test correlated with increased all-cause mortality, including cancer-related deaths. Among more than 4,800 participants diagnosed before 2015, infected individuals had a 4.5-fold higher risk of death from any cause and a 2.6-fold higher risk after excluding COVID-19 deaths. Cancer mortality was nearly twice as high in the first months post-infection.
Flatiron Health data from over 36,800 breast cancer patients indicated that COVID-19 infection after diagnosis was associated with a 44% increase in lung metastasis risk.
Conclusion
Respiratory viral infections can increase the risk of awakening dormant tumor cells in the lungs and driving metastasis in cancer survivors. Existing treatments for severe COVID-19 – including IL-6 receptor–targeting antibodies and oral JAK1/2 inhibitors – may help prevent virus-induced metastatic progression. However, their efficacy, safety, and optimal timing to avoid interfering with infection resolution require thorough evaluation in preclinical and clinical studies.
Reference
Respiratory viral infections awaken metastatic breast cancer cells in lungs
