Immune-Mitochondrial Crosstalk in Pancreatic Adenocarcinoma: Systematic Identification of Prognostic Biomarkers Through Immune Dictionary Framework

Introduction: Pancreatic adenocarcinoma (PAAD) is characterized by aggressive progression, driven by an immunosuppressive tumor microenvironment (TME) and mitochondrial dysfunction. Alterations in mitochondrial bioenergetics and metabolic reprogramming are crucial to tumor survival, invasion, and immune evasion. The "immune dictionary" approach provides a systematic classification of immune-related genes, offering insights into immune dysfunction and its interaction with mitochondrial pathways in the context of PAAD outcomes. Methods: To identify differentially expressed genes (DEGs) associated with immune dysfunction and mitochondrial pathways in PAAD, data from TCGA, GTEx, and three GEO datasets were integrated. Differential gene expression was analyzed using DESeq2, applying criteria of p-value < 0.05 and |log2 fold change| > 1. Using the "immune dictionary" framework, a prognostic model was developed through LASSO-Cox regression, followed by survival analysis for validation. The expression of key genes identified in the bioinformatics analysis was validated by quantitative real- time PCR (qPCR) on paired PAAD tissue and adjacent normal samples, focusing on NOG, TNFSF9, and TNFSF10. Results: Fifty-two DEGs associated with immune and mitochondrial dysfunction were identified. Gene set enrichment analysis revealed critical pathways, including IL-4 signaling, NF-κB activation, and autophagy. The LASSO-Cox model identified 12 prognostic genes that effectively stratified patients into high- and low-risk groups with high predictive accuracy. Validation confirmed significant differential expression patterns, consistent with computational findings. Discussion: This study, utilizing the immune dictionary framework, systematically analyzed immune- related and mitochondria-related genes in PAAD, identifying 12 DEGs for prognostic modeling. It revealed significant correlations between immune evasion and mitochondrial dysfunction, offering novel targets for personalized therapy. Conclusion: This study presents an innovative immune dictionary approach to identify key immune- and mitochondria-related DEGs in PAAD, providing potential targets for new therapeutic strategies and personalized treatment approaches. .