A 23-gene multi-omics signature predicts prognosis and treatment response in non-small cell lung cancer.

backgroundWe developed the first multi-omics prognostic signature integrating 19 programmed cell death (PCD) pathways and organelle functions (mitochondria, lysosomes, Golgi apparatus) to predict prognosis and immunotherapy response in non-small cell lung cancer (NSCLC). (2) Methods: By combining single-cell RNA-seq, bulk transcriptomics, and deep neural networks (DNN), we identified a 23-gene signature validated across four cohorts (AUC 0.696–0.812). Conducted MR analysis to explore causal links between signature genes and NSCLC incidence, providing biological insights. (3) Results: A prognostic signature was developed, including 23 prognostic genes related to 19 PCD patterns and three organelle functions. The signature demonstrated powerful performance in predicting NSCLC prognosis, immune in-filtration, and therapeutic response. Established DNN models showed high value in predicting risk score groupings of NSCLC. MR analysis for combined SNP information of the 23 prognostic genes suggested a link to the high incidence of NSCLC. Individual MR analysis showed that HIF1A and SQLE expression had a causal effect on NSCLC incidence. (4) Conclusion: This signature stratifies high-risk patients with immunosuppressive microenvironments and predicts enhanced sensitivity to gemcitabine and PD-1 inhibitors, offering a roadmap for personalized NSCLC management.