Low protein Diet Enhances AntiTumor Immunity and Immunotherapy through Microbiota Derived UDPgalactose in Pancreatic Cancer

The rising incidence of pancreatic ductal adenocarcinoma poses a significant threat to global health, with immunotherapies showing minimal efficacy due to the immunosuppressive nature of its tumor microenvironment. Our study aims to explore the potential of a low protein diet to modulate the gut microbiota and its metabolites, focusing on the impact on PDAC progression and response to immunotherapy. Our findings demonstrate that a 25% reduction in dietary protein intake effectively attenuates PDAC development and boosts anti-tumor immunostimulatory tumor associated macrophage phenotype. Concurrently, we observed a significant increase in the abundance of Blautia coccoides and its metabolite, uridine diphosphate-galactose with LPD intervention. Mechanistically, UDPgalactose activates the P2Y14R receptor, promoting STAT1 expression and phosphorylation, which induces an immunostimulatory macrophage phenotype. This dietary intervention and the associated microbiota changes enhance the sensitivity of PDAC to antiPD1 therapy. Finally, this work reveals that reduced fecal B. coccoides and serum UDPgalactose levels in patients with advanced pancreatic cancer, compared to the early stage patients. These findings reveal that LPD reshapes the gut microbiota and metabolites to induce the antitumor immunity via UDPgalactose/P2Y14R/STAT1 axis, enhances the efficacy of immunotherapy and survival rates in PDAC.