Respiratory viral infections prime accelerated lung cancer growth

SUMMARY The COVID-19 pandemic has highlighted long-term health concerns of viral pneumonia, yet its potential impact on cancer development and growth remains poorly understood. Here, we demonstrate that prior infection with SARS-CoV-2 or influenza virus promoted lung tumor progression by reprogramming the local immune landscape. Retrospective clinical analysis revealed that patients hospitalized with COVID-19 exhibited increased lung cancer incidence. Using multiple murine lung cancer models, we show that prior severe respiratory viral infections accelerated tumor growth and reduced survival. Mechanistically, prior viral pneumonia epigenetically remodeled the lung to establish a pro-tumor microenvironment, including the local accumulation of SiglecF hi tumor-associated neutrophils, a transcriptionally reprogrammed, immunosuppressive population whose signature predicted poor prognosis in human lung adenocarcinoma. In parallel, epithelial compartments exhibited altered differentiation trajectories, with persistence of injury-associated alveolar intermediates positioned along tumorigenic lineages. We observe sustained chromatin remodeling at key cytokine loci in immune and structure cells, linking inflammatory memory to persistent immune suppression. Therapeutically, combined inhibition of neutrophil recruitment via CXCR2 and PD-L1 signaling restored CD8⁺ T cell infiltration and suppressed tumor growth. Together, our findings establish a direct causal relationship between viral pneumonia, including COVID-19, and lung tumorigenesis, highlighting the urgent need to monitor survivors for elevated cancer risk and to develop targeted interventions and therapies aimed at preventing potential cancer bursts in COVID-19 convalescents. Graphic Abstract