Deployment related respiratory exposures (DRREs) during the Gulf War are now presumed to be linked to the development of lung cancer and other respiratory diseases. Recently, we employed a unique mouse model of experimental burn pit-type airborne toxin exposures and found that this induced prolonged inflammation and epigenetic alterations regulating key cancer associated pathways in alveolar macrophages. Unfortunately, there is limited research that examines the link between toxic respiratory exposures and an increased risk for developing lung cancer. Our objective is to determine the pathobiology of how DRREs predispose Veterans to lung cancer. To do this, we will (1) identify cancer-associated epigenetic alterations in lung tissue from Veterans deployed during the Gulf War who developed lung cancer, (2) employ digital spatial profiling to generate a transcriptional atlas of effected lung tissues from Gulf War Veterans to inform immune-mediated remodeling of the lung, (3) use a mouse model to determine how aerosolized gulf war toxins increase susceptibility to lung cancer, and (4) reverse the harmful epigenetic changes in cancer promoting pathways in 3D lung culture systems and primary cells from Veterans and following experimental aerosolized toxin exposures in mice. We will use this information to define the epigenetic alterations from DRREs that promote lung cancer, develop a grading system based on durable epigenetic marks identified in immune cells, and identify targetable epigenetic changes to potentially reduce the risk for developing lung cancer. Ultimately, if this project is successful we will better understand the mechanisms that underlie the development of lung cancer for deployed Gulf War Veterans. This will improve options for therapy and possibly a way to screen Veterans for an increased risk for developing lung cancer. Importantly, the findings may have broader implications for military service members deployed to the Persian Gulf, Southwest Asia and Afghanistan, as well as those in similar theatres of operation in the future.