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

ABSTRACT: Low-protein diets (LPD) have been linked to improved metabolic health, but their role in pancreatic ductal adenocarcinoma (PDAC) immunotherapy remains unclear. Here we show that an LPD suppresses PDAC progression in male mice by remodeling the gut microbiota and activating anti-tumor immunity. LPD promoted immune activation and drove an immunostimulatory tumor-associated macrophage (TAM) phenotype. Microbiota depletion abolished these anti-tumor effects, and fecal microbiota transplantation (FMT) from LPD-fed donors transferred the protective phenotype to recipient mice. Mechanistically, LPD enriched the commensal bacterium Blautia coccoides, which produced UDP-galactose that activated the macrophage P2Y14R/STAT1 axis, upregulating STAT1 expression and inducing an immunostimulatory phenotype. Combining LPD, B. coccoides, or UDP-galactose with anti-PD1 therapy improved survival beyond anti-PD1 alone. In patients with advanced PDAC, reduced fecal B. coccoides and serum UDP-galactose levels correlated with poor clinical outcomes. These findings establish that LPD reshapes the gut microbiota and its metabolites to enhance anti-tumor immunity via the UDP-galactose/P2Y14R/STAT1 axis, offering a potential dietary strategy to improve PDAC immunotherapy responses and survival.

INSTRUMENT(S): Liquid Chromatography MS - alternating - hilic, Liquid Chromatography MS - alternating - reverse-phase

PROVIDER: MTBLS14989 | MetaboLights | 2026-07-09

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS14989_LC-MS_alternating_hilic-1.txt	Txt
	a_MTBLS14989_LC-MS_alternating_reverse-phase.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS14989_LC-MS_alternating_hilic_v2_maf.tsv	Tabular
	m_MTBLS14989_LC-MS_alternating_reverse-phase_v2_maf.tsv	Tabular

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Project description:Immunotherapeutics represent highly promising agents with the potential to improve patient outcomes in a variety of cancer types. Unfortunately, single-agent immunotherapy has achieved limited clinical benefit to date in patients suffering from pancreatic ductal adenocarcinoma (PDAC). This may be due to the presence of a uniquely immunosuppressive tumor microenvironment (TME) present in PDACs, which creates a barrier to effective immune surveillance. Critical obstacles to immunotherapy in PDAC tumors include the dense desmoplastic stroma that acts as a barrier to T-cell infiltration and the high numbers of tumor-associated immunosuppressive cells. We have identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as a significant regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlates with high levels of fibrosis and poor CD8+ cytotoxic T-cell infiltration. Single-agent FAK inhibition (VS-4718) dramatically limited tumor progression, resulting in a doubling of survival in the p48-Cre/LSL-KrasG12D/p53Flox/+ (KPC) mouse model of human PDAC. This alteration in tumor progression was associated with dramatically reduced tumor fibrosis, decreased numbers of tumor-infiltrating immature myeloid cells and immunosuppressive macrophages. We postulated that these desirable effects of FAK inhibition on the TME might render PDAC tumors more sensitive to immunotherapy. Accordingly, we found that VS-4718 rendered the previously unresponsive KPC mouse model responsive to anti-PD1 and anti-CTLA4 antagonists leading to a nearly tripling of survival times. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME thus rendering tumors more responsive to immunotherapy. We treated KP orthotopic tumor-bearing mice with vehicle and FAK inhibitor (FAKi) for 14 days, then extracted total RNA from tumor tissues.

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

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