Metabolic reprogramming shapes the immune microenvironment in pancreatic adenocarcinoma: prognostic implications and therapeutic targets.

Introduction: Pancreatic adenocarcinoma (PAAD) is characterized by a profoundly immunosuppressive tumor microenvironment (TME) that limits the efficacy of immunotherapy. Emerging evidence suggests that tumor-specific metabolic reprogramming may drive disease progression and shape the immune landscape in PAAD. Methods: We integrated multi-omics data from TCGA, GEO, and ICGC to identify key metabolism-related genes (MRGs) that influence immune cell infiltration, tumor progression, and patient survival. Based on nine pivotal MRGs (including ANLN, PKMYT1, and HMGA1), we developed and validated a novel metabolic-prognostic index (MPI). Functional enrichment analyses were conducted to elucidate the metabolic pathways associated with different MPI risk groups. Results: The MPI effectively stratified patients into high- and low-risk groups. High-MPI scores correlated with poor overall survival, elevated tumor mutation burden (TMB), and an immunosuppressive TME, evidenced by reduced CD8⁺ T-cell infiltration and increased expression of immune checkpoints (PD-L1, TGF-β). Functional enrichment revealed glycolysis and folate biosynthesis as dominant pathways in high-MPI groups, whereas fatty acid metabolism prevailed in low-MPI groups. Experimental validation underscored the role of ANLN in promoting epithelial-mesenchymal transition (EMT) and immune evasion via NF-κB signaling. ANLN knockdown significantly reduced glycolytic activity, tumor cell migration, and immune evasion. Drug sensitivity analyses indicated resistance to gemcitabine but sensitivity to afatinib in high-MPI patients. Although TIDE analysis predicted immune checkpoint inhibitor (ICI) resistance in high-MPI tumors, a subset of patients showed favorable responses to anti-PD-L1 therapy. Discussion: These findings provide a comprehensive framework for understanding how metabolic reprogramming shapes PAAD's immunosuppressive TME and affects treatment outcomes. By accurately stratifying patients, the MPI serves as a promising tool to guide therapeutic decisions, including targeted therapy selection and immunotherapy prediction, ultimately offering potential for more personalized management of PAAD.