Analysis of the Potential Mediating Role of Plasma Proteins in the Association Between Air Pollution Exposure and Lung Cancer Risk Among Ever-Smokers

The biological mechanisms linking air pollution to lung carcinogenesis remain underexplored. This study aimed to identify key proteins and pathways involved in mediating the effects of air pollutants on lung cancer risk. We analyzed 95 matched lung cancer case–control pairs of ever-smokers with prediagnosis plasma protein profiles measured in the Cancer Prevention Study-II Nutrition Cohort. We assessed associations between protein levels and six individual air pollutants, air pollution mixture, and lung cancer risk, adjusting for confounders and multiple testing. We identified overlapping proteins and enriched pathways associated with both exposures and lung cancer risk, followed by an exploratory high-dimensional mediation analysis (HIMA) to investigate the potential mediating roles of proteins. Seventeen proteins were associated with both exposures and lung cancer, including CX3CL1, ADAM15, and CXCL17 (P < 0.05). HIMA identified six proteins, including CX3CL1 and CXCL17, as potential mediating proteins of individual pollutant-lung cancer associations (Bonferroni-corrected P < 0.05), while these findings did not remain significant when excluding cases diagnosed within one year of blood draw. The exploratory results suggest that proteins and pathways related to inflammatory chemokine signaling, immune modulation, and altered cell proliferation, migration, and survival may play significant roles in air pollution-lung cancer association among ever-smokers.