Low-Protein Diet Enhances Anti-Tumor Immunity and Immunotherapy through Microbiota-Derived Uridine Diphosphate-Galactose in Pancreatic Cancer

This study explored the potential of a low-protein diet (LPD) to modulate the gut microbiota, focusing on pancreatic ductal adenocarcinoma (PDAC) progression and response to immunotherapy. A 25% reduction in dietary protein intake attenuated PDAC development, drove immune activation in the tumor microenvironment (TME) and boosted the immunostimulatory tumor-associated macrophages (TAMs) phenotype. We found the depletion of gut microbiota compromised the anti-tumor effect of LPD. Specifically, a significant increase in the abundance of Blautia coccoides was observed following LPD intervention. Further studies revealed that Blautia coccoides administration inhibited PDAC tumorigenesis and via its metabolite, uridine diphosphate (UDP)-galactose. Mechanistically, UDP-galactose activates the P2Y14R receptor, promoting STAT1 expression and phosphorylation, inducing an immunostimulatory macrophage phenotype. Combining LPD with α-PD1 significantly attenuated tumor burden and improved survival beyond α-PD1 alone. Finally, reduced fecal B. coccoides and serum UDP-galactose were observed in patients with advanced pancreatic cancer. In summary, LPD reshapes the gut microbiota and metabolites to induce anti-tumor immunity via the UDP-galactose/P2Y14R/STAT1 axis, enhancing survival rates in PDAC.