Lung Cancer in Never Smokers: Genetics, Epidemiology, Environmental Exposures, and Distinct Immune Landscape.

Lung cancer in never smokers (LCINS) disproportionately affects younger women and East Asian populations and is characterized by distinct genetic susceptibility, environmental exposures, and molecular alterations. However, never smokers remain excluded from current screening guidelines despite rising incidence and identifiable high-risk subgroups. Family history confers substantial risk, with affected first-degree relatives showing 1.7-fold higher incidence, while genome-wide association studies and polygenic risk scores further refine genetic susceptibility. Female sex and Asian ethnicity are primary independent risk factors, exceeding family history in multivariable analysis. Asian never smokers have a 2.3-fold higher baseline incidence of lung cancer than non-Asian never smokers, and Asian female never smokers exhibit lung cancer detection rates comparable to Asian male ever smokers. Screening trials in never smokers demonstrated detection rates comparable to smoker-based trials, suggesting certain demographic subgroups may reach risk thresholds where screening could be beneficial. Environmental PM exposure increases LCINS incidence and mortality in East Asian populations where both PM exposure and EGFR mutation rates are elevated. Recent evidence implicates mitochondrial DNA mutations in LCINS susceptibility among Asian never smokers, suggesting integration of environmental exposures and molecular biomarkers may improve risk stratification for screening. The high prevalence of actionable oncogenic drivers in LCINS underscores the importance of early detection, as these tumors benefit from targeted therapies whereas immune checkpoint inhibitors responses are often lower. This review summarizes LCINS epidemiology, genetic susceptibility, molecular alterations, environmental risk factors, and tumor immunology, highlighting the need for greater focus on this underrecognized and growing patient population.