Respiratory viral infections awaken metastatic breast cancer cells in lungs

Shi B. Chia, Bryan J. Johnson, Junxiao Hu, Felipe Valença-Pereira, Marc Chadeau-Hyam, Fernando Guntoro, Hugh Montgomery, Meher P. Boorgula, Varsha Sreekanth, Andrew Goodspeed, Bennett Davenport, Marco De Dominici, Vadym Zaberezhnyy, Wolfgang E. Schleicher, Dexiang Gao, Andreia N. Cadar, Lucia Petriz-Otaño, Michael Papanicolaou, Afshin Beheshti, Stephen B. Baylin, Joseph W. Guarnieri, Douglas C. Wallace, James C. Costello, Jenna M. Bartley, Thomas E. Morrison, Roel Vermeulen, Julio A. Aguirre-Ghiso, Mercedes Rincon and James DeGregori ()
Additional contact information
Shi B. Chia: University of Colorado Anschutz Medical Campus
Bryan J. Johnson: University of Colorado Anschutz Medical Campus
Junxiao Hu: University of Colorado Anschutz Medical Campus
Felipe Valença-Pereira: University of Colorado Anschutz Medical Campus
Marc Chadeau-Hyam: Utrecht University
Fernando Guntoro: Imperial College London
Hugh Montgomery: University College London
Meher P. Boorgula: University of Colorado Anschutz Medical Campus
Varsha Sreekanth: University of Colorado Anschutz Medical Campus
Andrew Goodspeed: University of Colorado Anschutz Medical Campus
Bennett Davenport: University of Colorado Anschutz Medical Campus
Marco De Dominici: University of Colorado Anschutz Medical Campus
Vadym Zaberezhnyy: University of Colorado Anschutz Medical Campus
Wolfgang E. Schleicher: University of Colorado Anschutz Medical Campus
Dexiang Gao: University of Colorado Anschutz Medical Campus
Andreia N. Cadar: University of Connecticut School of Medicine and UConn Health
Lucia Petriz-Otaño: Albert Einstein College of Medicine
Michael Papanicolaou: Albert Einstein College of Medicine
Afshin Beheshti: COVID-19 International Research Team
Stephen B. Baylin: COVID-19 International Research Team
Joseph W. Guarnieri: The Children’s Hospital of Philadelphia
Douglas C. Wallace: The Children’s Hospital of Philadelphia
James C. Costello: University of Colorado Anschutz Medical Campus
Jenna M. Bartley: University of Connecticut School of Medicine and UConn Health
Thomas E. Morrison: University of Colorado Anschutz Medical Campus
Roel Vermeulen: Utrecht University
Julio A. Aguirre-Ghiso: Albert Einstein College of Medicine
Mercedes Rincon: University of Colorado Anschutz Medical Campus
James DeGregori: University of Colorado Anschutz Medical Campus

Nature, 2025, vol. 645, issue 8080, 496-506

Abstract: Abstract Breast cancer is the second most common cancer globally, with most deaths caused by metastatic disease, often following long periods of clinical dormancy1. Understanding the mechanisms that disrupt the quiescence of dormant disseminated cancer cells (DCCs) is crucial for addressing metastatic progression. Infections caused by respiratory viruses such as influenza and SARS-CoV-2 trigger both local and systemic inflammation2,3. Here we demonstrate, in mice, that influenza and SARS-CoV-2 infections lead to loss of the pro-dormancy phenotype in breast DCCs in the lung, causing DCC proliferation within days of infection and a massive expansion of carcinoma cells into metastatic lesions within two weeks. These phenotypic transitions and expansions are interleukin-6 dependent. We show that DCCs impair lung T cell activation and that CD4+ T cells sustain the pulmonary metastatic burden after the influenza infection by inhibiting CD8+ T cell activation and cytotoxicity. Crucially, these experimental findings align with human observational data. Analyses of cancer survivors from the UK Biobank (all cancers) and Flatiron Health (breast cancer) databases reveal that SARS-CoV-2 infection substantially increases the risk of cancer-related mortality and lung metastasis compared with uninfected cancer survivors. These discoveries underscore the huge impact of respiratory viral infections on metastatic cancer resurgence, offering new insights into the connection between infectious diseases and cancer metastasis.

Date: 2025
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DOI: 10.1038/s41586-025-09332-0

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