Unraveling the molecular mechanisms of smoking-associated non-small cell lung cancer: a comprehensive analysis of genetic, therapeutic, and immunological.

BACKGROUND

Cigarette smoking is a well-established primary risk factor for the development of non-small cell lung cancer (NSCLC). However, the molecular heterogeneity and therapeutic implications among patients with diverse smoking statuses have not been thoroughly investigated. This study aims to investigate the predictive role of smoking in NSCLC, its molecular mechanism and tumor microenvironment.

METHODS

Public databases were utilized to obtain information on NSCLC patients. A cohort of 1,087 patients was used for genomic and survival analysis. There were 321 patients who received immunotherapy included in the efficacy analysis.

RESULTS

In patients with lung squamous cell carcinoma (LUSC) and in immunotherapy-treated NSCLC patients, reformed smokers demonstrated superior survival outcomes compared to current smokers and never smokers. Notably, distinct genetic mutations were identified across different smoking statuses: never smokers exhibited a higher prevalence of EGFR mutations, while reformed smokers and current smokers displayed a higher incidence of TP53 mutations. Moreover, current smokers achieved enhanced benefit from specific level A drugs. The tobacco-related mutational signature (SBS4) and APOBEC mutational signatures (SBS2 and SBS13) were detected across all groups. Regarding the immune microenvironment, M0 macrophages, showed recovery after smoking cessation. However, immature B cells, dendritic cells, lymphocytes, mast cells, plasma cells, and regulatory T cells (Tregs) maintained an immune signature even after smoking cessation.

CONCLUSIONS

This study elucidates the profound impact of smoking status on the molecular profile, treatment response, and tumor immune microenvironment in NSCLC patients. Additionally, our results reinforce the paramount importance of smoking cessation in enhancing patient prognosis and optimizing treatment efficacy.