Lung cancer remains the most common cause of cancer death globally . Dysregulation of immune response and inflammatory signaling is known to play an important role in lung tumorigenesis, but the causal drivers of this process have yet to be elucidated . To identify circulating inflammatory and immune-related proteins that influence risk for lung cancer we related genetically predicted plasma levels for 85 inflammation and immune proteins with susceptibility to lung cancer . Mendelian randomization (MR) analyses in 29,266 cases and 56,450 controls identified a candidate causal marker, IL-18, which conferred lower risk of lung cancer (OR per standard deviation increase : 0.85 [95% CI : 0.79-0.92] ), in particular for adenocarcinoma (OR : 0.80 [95% CI : 0.72-0.89] ). We subsequently validated this association using polygenic IL-18 predictions in the UK Biobank (HR highest vs. lowest quartile : 0.83 [95% CI : 0.72-0.95] ) and using pre-diagnostic blood concentrations of IL-18 in 732 cases and 732 controls after controlling for the inhibitory role of IL-18BP (OR highest vs. lowest quartile : 0.63 [95% CI : 0.41-0.91] ). Genetic colocalization suggested that IL-18 may act on lung cancer risk locally via lung tissue expression, and joint MR and tumor microenvironment analyses highlight CD8 T cells and NK cells as potential mediators . In addition to risk, IL-18 expression in adenocarcinoma tumor tissue was found to be associated with all-cause mortality in 480 TCGA samples after controlling for IL-18BP (HR per SD : 0.87 [95% CI : 0.78 , 0.98] ), which is in line with recent studies showing anti-tumor effects of IL-18 . Our comprehensive genomic triangulation study thus highlights the potential for IL-18 as an aetiological biomarker and targetable for immune-oncology therapies.