Low-protein diet enhances antitumor immunity in pancreatic cancer through microbiota-derived UDP-galactose.

Dietary interventions can influence cancer progression, yet the role of low-protein diets (LPDs) in pancreatic ductal adenocarcinoma (PDAC) immunotherapy is unclear. Here we show that an LPD suppresses PDAC progression in male mice by remodeling the gut microbiota and activating antitumor immunity. LPD promoted immune activation and drove an immunostimulatory tumor-associated macrophage phenotype. Microbiota depletion abolished these effects and fecal microbiota transplantation from LPD-fed donors transferred the protective phenotype to recipients. Mechanistically, LPD enriched Blautia coccoides, which produced uridine diphosphate (UDP)-galactose to activate the macrophage P2Y14R-STAT1 axis, inducing an immunostimulatory phenotype. Combining LPD, B. coccoides or UDP-galactose with anti-PD1 improved survival over anti-PD1 alone. In persons with advanced PDAC, reduced fecal B. coccoides and serum UDP-galactose correlated with poor outcomes. These findings establish that LPD reshapes the gut microbiota and metabolites to enhance antitumor immunity through the UDP-galactose-P2Y14R-STAT1 axis, offering a dietary strategy to improve PDAC immunotherapy.