Lactylation profiling reveals novel biomarkers and immune interactions in pancreatic cancer

• First characterize the global lactylation profiling in pancreatic cancer tissues, identifying metabolism- and immune-related differential lactylation sites. • Discover and validate novel lactylation-derived biomarkers for predicting prognosis and immunotherapy response in pancreatic cancer patients independently. • Uncover a new mechanism of lactylation regulating the tumor immune microenvironment in pancreatic cancer, providing new targets for TIME-targeted therapies. Pancreatic cancer, known for its aggressive nature and poor prognosis, often eludes early detection and effective treatment. This study investigates the underexplored terrain of protein lactylation in pancreatic cancer to identify potential biomarkers and understand its immunological implications. Proteomic and transcriptomic analyses were conducted to profile lactylation changes, identifying 11 upregulated and 1 downregulated lactylation-related proteins. Intersection analysis between proteomics and transcriptomics highlighted four key genes (COQ9, GAA, LYST and TP53) with consistent expression trends, suggesting their central role in the lactylation pathway within pancreatic cancer. ROC curve analysis underscored the diagnostic potential of GAA and LYST, with AUCs over 0.9. Further, ssGSEA revealed significant correlations between these core genes and various immune cells, indicating an immune-modulatory role. Notably, most core lactylation-related genes were positively associated with immune checkpoint molecules, barring COQ9. GSEA of gene expression groups delineated three conserved upregulated KEGG pathways, with additional REACTOME pathway analysis uncovering 68 conserved pathways. These findings highlight lactylation’s involvement in pancreatic cancer progression and its possible exploitation for diagnostic and therapeutic advancements.