A landmark prospective study analyzing oral microbiomes of over 122,000 participants identified 27 bacterial and fungal species associated with a 3.5-fold increased risk of pancreatic cancer. The large-scale metagenomic and mycobiome analyses suggest that oral microbial profiles could serve as effective biomarkers for pancreatic cancer risk stratification. These findings open avenues for early detection and personalized prevention strategies against a cancer with notoriously poor prognosis.