• Different environmental exposures are closely associated with specific proteomic variations at the individual level. • Environmental exposures and related proteomic features exhibit associations with lung cancer risk. • Multiple environment-linked proteins are predominantly enriched in inflammatory and immune pathways. • Different environmental exposures were associated with lung cancer risk alongside both exposure-specific proteomic scores and several shared candidate proteins (ANGPT2, CEACAM5, and TNFSF13B). Mounting evidence indicates that environmental factors such as air pollution, residential neighborhood greenness, traffic emissions, and socioeconomic conditions may influence lung cancer development, yet the molecular correlates underlying these associations remain incompletely characterized. Proteomics provides an innovative approach to map circulating protein signatures linked to environmental exposures and lung cancer. This prospective cohort study, utilizing data from the UK Biobank, integrated 14 environmental exposures with plasma proteomic data comprising 2,923 proteins measured in 42,058 participants. Exposure-related proteins were identified and analyzed for functional pathway enrichment. Proteomic scores were generated using LASSO regression. Cox regression and counterfactual-based mediation analyses were conducted to assess the association with lung cancer risk and explore potential indirect association patterns of both proteomic scores and specific proteins in the exposure-disease pathways. Significant variations were observed in circulating proteins associated with environmental changes. Environment-associated proteins were mainly enriched in pathways related to inflammation and immune regulation. These exposures (PM 2.5 , PM 10 , benzene, NDVI, EVI, and TDI) and their related proteomic scores showed significant associations with lung cancer risk. Mediation analyses revealed that proteomic scores explained substantial proportions of the exposure–cancer associations, and several individual proteins, including ANGPT2, CEACAM5, and TNFSF13B, emerged as candidate proteins showing consistent indirect associations across multiple exposures. This large-scale cohort study demonstrates that environmental exposure data are associated with distinct proteomic alterations and that these exposure-related proteomic signatures are associated with lung cancer risk. By mapping pathway-level signals and candidate proteins potentially involved in these associations, our findings provide hypothesis-generating insights into links between environmental exposures and lung cancer risk and offer valuable insights for environmental carcinogenesis research and precision prevention strategies. Created in BioRender. Zhang, Y. (2025) https://BioRender.com/89yj3ii
Zhu et al. (Sun,) studied this question.