Lung adenocarcinoma (LUAD) has a poor prognosis. This study aimed to screen core genes associated with the tumor microenvironment (TME) and programmed cell death (PCD) to provide new prognostic markers and therapeutic targets for LUAD, and to validate their cross-species conservation. Methods Based on RNA-seq data for LUAD and normal lung tissue in The Cancer Genome Atlas (TCGA) database, we assessed the TME and screened for differentially expressed genes (DEGs) using the ESTIMATE algorithm. Functional enrichment analysis (Gene Ontology/Kyoto Encyclopedia of Genes and Genomes), protein-protein interaction (PPI) networks, and univariate Cox regression analysis were performed on the DEGs. Cross-screening combining PPI networks, univariate Cox regression, and the PCD genome was employed to identify core prognostic genes, and their prognostic value and TME association were validated by survival analysis, gene set enrichment analysis (GSEA), and immune infiltration (CIBERSORT) analysis.

High immune/ESTIMATE scores were significantly associated with prolonged patient survival. The selected shared DEGs were primarily enriched in immune-related pathways. Cross-analysis identified CD19 and CD79A as core prognostic genes associated with PCD. Clinical-feature analysis showed that CD19 and CD79A expression were significantly higher in LUAD tumors than in normal lung tissues, but their expression levels decreased significantly with advancing TNM staging, closely associated with advanced staging, distant metastasis, and poor prognosis. Patients with high CD19/CD79A expression had significantly longer overall survival than those with low expression. Animal-model validation confirmed the cross-species conserved role of CD19/CD79A in tumor progression. GSEA indicated that the high-CD19/CD79Aexpression group was significantly enriched in immune activation pathways (e. g. , allograft rejection, complement response), while the low-expression group was enriched in metabolic (glycolysis, oxidative phosphorylation) and oncogenic pathways. CIBERSORT analysis confirmed that their expression levels were significantly positively correlated with TME immune activity. Conclusions CD19 and CD79A are overexpressed in LUAD tumor tissues, but their expression levels decrease with disease progression. High expression of CD19/CD79A is closely associated with a favorable prognosis and immune-activated TME, while low expression suggests a poor prognosis and immune suppression/oncogenic states. As genes associated with PCD, CD19/CD79A may serve as potential protective prognostic biomarkers and immunotherapeutic targets in LUAD, thereby providing a basis for understanding the immune mechanisms of LUAD and guiding the development of B cell-targeted therapeutic strategies.