Background: Recent studies have unveiled disulfidptosis as a phenomenon intimately associated with cellular damage, heralding new avenues for exploring tumor cell dynamics. We aimed to explore the impact of disulfide cell death on the tumor immune microenvironment and immunotherapy in lung adenocarcinoma (LUAD). Methods: We initially utilized pan-cancer transcriptomics to explore the expression, prognosis, and mutation status of genes related to disulfidptosis. Using the LUAD multi- -omics cohorts in the TCGA database, we explore the molecular characteristics of subtypes related to disulfidptosis. Employing various machine learning algorithms, we construct a robust prognostic model to predict immune therapy responses and explore the model's impact on the tumor microenvironment through single-cell transcriptome data. Finally, the biological functions of genes related to the prognostic model are verified through laboratory experiments. Results: Genes related to disulfidptosis exhibit high expression and significant prognostic value in various cancers, including LUAD. Two disulfidptosis subtypes with distinct prognoses and molecular characteristics have been identified, leading to the development of a robust DSRS prognostic model, where a lower risk score correlates with a higher response rate to immunotherapy and a better patient prognosis. NAPSA, a critical gene in the risk model, was found to inhibit the proliferation and migration of LUAD cells. Conclusion: Our research introduces an innovative prognostic risk model predicated upon disulfidptosis genes for patients afflicted with Lung Adenocarcinoma (LUAD). This model proficiently forecasts the survival rates and therapeutic outcomes for LUAD patients, thereby delineating the high-risk population with distinctive immune cell infiltration and a state of immunosuppression. Furthermore, NAPSA can inhibit the proliferation and invasion capabilities of LUAD cells, thereby identifying new molecules for clinical targeted therapy.

Lung adenocarcinoma (LUAD), a subtype of non-small cell lung cancer (NSCLC), has high incidence and poor prognosis. Although anti-programmed cell death protein 1 (PD1) therapy and epidermal growth factor receptor (EGFR) inhibitors benefit some patients, many remain unresponsive. Genome-wide association studies (GWAS) can identify risk loci, while single-cell transcriptomics enables exploration of genetic variations and mechanisms in LUAD. We integrated GWAS data from FinnGen, IEU OpenGWAS, and GWAS Catalog with single-cell and spatial transcriptomics from GEO to investigate LUAD genetics and pathology. GWAS analyses identified SNP loci, risk factors, LD Score, and SMR results, revealing a novel apoptosis-related locus, Serine/Threonine Kinase 24 (STK24) (SMR P < 0.05). Single-cell analysis identified STK24-positive epithelial cells (STK24posEpi) and their transcription factors (SCENIC), developmental trajectory (Monocle), and tumor microenvironment roles (CellCall). Spatial mapping (RCTD) and trajectory analysis (stlearn) were combined with cell communication (CellChat), spatial signal flow (Commot), and co-localization (Misty). Bayesian deconvolution linked STK24posEpi to TCGA-LUAD bulk transcriptomes, assessing overall survival (OS), immune infiltration, and clinical traits. A prognostic model (STK24SuperPC, mean c-index 0.61) was built using multiple machine learning algorithms to predict survival and immunotherapy response. Laboratory experiments tested STK24’s effects on LUAD cell proliferation and apoptosis. STK24 was identified as a LUAD risk factor (pSMR < 0.05). STK24posEpi communicated with fibroblasts, endothelial cells, and others via MIF and PDGF pathways, and was associated with apoptosis (Importance > 0.5), metastasis (Importance > 2), DNA repair (Importance > 1), and DNA damage (Importance > 2). Located at the origin of the trajectory, STK24posEpi correlated with poor prognosis (HR > 0, P < 0.05) and reduced lymphocyte infiltration (Pearson’s r < 0, P < 0.05). STK24 overexpression enhanced LUAD cell proliferation, migration, and colony formation, while reducing apoptosis, increasing BCL-2 and Caspase-3, and decreasing Cleaved-Caspase-3 expression. STK24, an apoptosis-related gene, promotes LUAD progression by enhancing proliferation and inhibiting apoptosis, with STK24posEpi interacting in the tumor microenvironment through PDGF and MIF pathways. These findings offer potential therapeutic targets and support personalized LUAD treatment strategies.