Abstract
BACKGROUND: Immune checkpoint inhibitors (ICIs) have significantly improved outcomes in non-small cell lung cancer (NSCLC), yet their use is associated with a notable risk of immune-related adverse events, including checkpoint inhibitor–associated pneumonitis (CIP). The real-world incidence, risk magnitude, and underlying immunopathogenesis of CIP in NSCLC remain inadequately defined. METHODS: We conducted a retrospective cohort study using electronic health records from 21,671 NSCLC patients, categorized into ICI (n = 8,744) and non-ICI (n = 12,927) groups. Incidence of pneumonitis was evaluated using propensity score–matched analysis, Kaplan-Meier curves, and Cox regression models. Subgroup analyses were performed across demographic and clinical variables. Differentially expressed genes (DEGs) from transcriptomic datasets were analyzed to explore inflammatory mechanisms, including GO/KEGG pathway enrichment, protein–protein interaction (PPI) network construction, and single-sample gene set enrichment analysis (ssGSEA). RESULTS: The incidence of pneumonitis was significantly higher in the ICI group (28.9%) compared to the non-ICI group (10.0%) (hazard ratio [HR] = 2.86; 95% confidence interval [CI], 2.43–3.29; P < 0.001). This elevated risk persisted across age, sex, BMI, comorbidities, and autoimmune status. Transcriptomic analysis revealed distinct upregulation of immune-related genes (e.g., TCF7L1, ATP1B4, RPL18A), with enrichment of pathways including IFN-γ signaling, Th17 differentiation, TNF and JAK-STAT signaling. ssGSEA confirmed increased immune activation scores in CIP samples. PPI network and hub gene analysis identified GHRH, ZBTB21, and PLAU as central regulators. CONCLUSIONS: ICI use in NSCLC is associated with a markedly increased risk of pneumonitis. Transcriptomic profiling suggests that overactivation of pro-inflammatory immune pathways underlies CIP pathogenesis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12890-025-04005-0.