Bioinformatics analysis identifies NT5M modulates immune evasion through PD-L1 via CXCL8 in pancreatic adenocarcinoma

Pancreatic adenocarcinoma (PAAD) is a highly aggressive and lethal malignancy, characterized by late diagnosis, rapid progression, and poor response to conventional therapies. Altered nucleotide metabolism has recently been recognized as a critical driver of tumorigenesis, impacting cellular proliferation, invasion, and immune evasion. However, the role of specific metabolic enzymes, such as NT5M (cytosolic 5'-nucleotidase, mitochondrial), in PAAD remains poorly understood. In this study, we employed an integrated approach combining comprehensive bioinformatics analysis with systematic in vitro functional assays to investigate the multifaceted roles of NT5M in PAAD. Our investigation focused on three key aspects: (1) establishing NT5M as a novel prognostic biomarker, with lower expression levels significantly correlating with poor clinical outcomes; (2) characterizing the association between NT5M expression and tumor microenvironment (TME) features; and (3) elucidating the mechanistic role of NT5M in immune regulation within PAAD. Importantly, we discovered that NT5M downregulation is associated with increased CXCL8 expression and subsequent PD-L1 upregulation, thereby reversing immune evasion in pancreatic cancer. These findings establish NT5M as both a valuable prognostic indicator for tumor progression and a promising therapeutic target for PAAD. The identification of these interconnected pathways provides a novel strategy for enhancing the efficacy of immune checkpoint blockade therapies, potentially overcoming the current limitations in pancreatic cancer immunotherapy.