Polyamines in pancreatic cancer: reshaping the immunosuppressive tumor microenvironment

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy, characterized by its aggressiveness and poor outcomes. Emerging evidence implicates dysregulated polyamine metabolism as a key driver of PDAC immunosuppression, yet the mechanisms underlying this metabolic-immune crosstalk remain poorly defined. This review summarizes recent findings demonstrating that PDAC is uniquely dependent on glutamine-derived ornithine for de novo polyamine synthesis, orchestrated by the KRAS-MYC axis. Through metabolic reprogramming of immune cells, polyamines polarize tumor-associated macrophages toward M2-like phenotypes, expand myeloid-derived suppressor cells, and impair T cell activation. Crucially, the immunomodulatory effects of polyamines are source-dependent: tumor-derived spermidine promotes T cell exhaustion, whereas dietary spermidine enhances antitumor immunity through fatty acid oxidation. Preclinical studies have highlighted that polyamine-targeted therapy, including biosynthesis inhibitors, arginine deprivation agents and polyamine analogue, is a promising strategy to reverse immunosuppression and enhance the efficacy of checkpoint inhibitors. These evidences establish polyamine metabolism as a therapeutic vulnerability in PDAC, offering novel diagnostic tools and combination regimens to overcome therapeutic resistance.