Distinct molecular pathways driving lung cancer in non-smokers: Etiology, signaling networks, and clinical...

Lung Cancer Non-smokers (LCNS) is a developing worldwide health issue. LCNS is caused by a different combination of environmental, genetic, and molecular variables than smoker-related lung cancer, necessitating a change in preventive and treatment approaches. Particularly among women and those living in contaminated metropolitan areas, the incidence is rising. Radon, indoor biomass fuels, occupational carcinogens, ambient air pollution, and novel contaminants are examples of non-tobacco dangers. These exposures create distinct molecular and epigenetic landscapes by promoting oxidative stress, inflammation, and DNA damage. Molecularly, LCNS usually exhibits no tobacco-related mutational markers and a modest tumor mutational load. Actionable drivers, including EGFR, ALK, ROS1, RET, and HER2, are frequently included. EGFR signaling, PI3K/AKT/mTOR, MAPK/ERK, Hippo-YAP/TAZ, ferroptosis, and non-coding RNA networks are among the controlled signaling pathways that frequently direct tumor formation rather than widespread genetic instability. Heterogeneity and resistance are facilitated by epigenetic remodeling and transcriptional flexibility, which enable tumors to adjust to their surroundings and treatment. This study compiles the current understanding of LCNS etiology, molecular characteristics, and signaling pathways and identifies gaps that hinder clinical translation. In order to capture exposure-molecule interactions, it emphasizes the necessity of combining environmental exposomics with multi-omics tumor profiling. Intratumoral heterogeneity may be resolved, exposure-specific cell states may be elucidated, and novel therapeutic targets may be identified through advances in single-cell and spatial omics. Precision oncology requires molecular and liquid biopsy biomarkers, as early diagnosis and LCNS-specific screening remain difficult in clinical practice. Pathway-focused treatments for non-smokers, environmental interventions, and exposure-informed risk models are some potential future possibilities. Research, prevention, and patient treatment are improved worldwide when LCNS is framed as a unique, environmentally driven illness.