Age and sex-dependent tumor microbiome programs shape pancreatic cancer prognosis

Pancreatic cancer prognosis is shaped by host factors and the tumor microenvironment. Here, we identify a survival advantage in young female (≤55 years) pancreatic cancer patients-absent in older patients and males. Integrated analysis of SEER and TCGA datasets reveals that host immune and inflammatory pathways associated with bacterial response are enriched in young males, old males, and old females, but notably absent in young females. Direct microbial profiling of 30 pancreatic tumors shows that young female tumors harbor a distinct microbiome with lower Staphylococcus abundance. Functional experiments in a murine model further demonstrate that Staphylococcus promotes tumor growth in an estrogen-dependent manner, providing experimental evidence consistent with the clinical association. Older female tumors exhibit distinct microbial metabolic pathways. Our findings suggest that age and sex jointly shape the pancreatic tumor microbiome, highlighting demographic-specific approaches in cancer microbiology.