Gut virus shapes distal tumor immunity: fecal phage transfer from long-term pancreatic cancer survivors delays tumor progression

Gut bacteria and fungi have been implicated in promoting tumor progression in patients with pancreatic ductal adenocarcinoma (PDAC). However, the role of the gut virus in PDAC pathogenesis remains poorly defined. Here, we systematically compared the fecal virus of long-term survivors (LTS) and short-term survivors (STS) of PDAC, and identified striking compositional differences between the two groups. Through fecal virus transplantation into murine orthotopic PDAC models, we demonstrated that the LTS-derived virus significantly delayed tumor progression. Mechanistically, LTS samples were characterized by a reduced abundance of Akkermansia muciniphila-targeting phages (Akkermannviridae), leading to significantly increased intestinal Akkermansia following transplantation compared to STS. Akkermansia -derived metabolite 2-PMPA exerted tumor-suppressive effects by promoting migration of intestinal group 3 innate lymphoid cells (ILC3s) into the tumor, where they modulated IL-17 signaling and enhanced CD8⁺ T cell infiltration, thereby orchestrating an anti-tumor immune response. Our study provides the first causal evidence that the gut virus can regulate the progression of pancreatic cancers through a bacteriophage-microbiota-metabolite-innate/adaptive immunity axis, offering new insights into microbiome-targeted interventions and immunotherapeutic strategies for distal tumors.