New Insights into Microbiome Metabolic Mechanisms for Pancreatic Cancer Therapy

PDAC remains a lethal malignancy with a dismal 5-year survival rate, largely due to pervasive chemoresistance. Emerging evidence suggests that microbiome-metabolism interactions are important contributors to therapy resistance in PDAC, extending traditional genome-centered models. However, the site-specific contributions of oral, gut, and intratumoral microbiota, their reciprocal interactions with host metabolic reprogramming, and the translational relevance of this crosstalk remain incompletely defined. The intratumoral, oral, and gut microbiomes exhibit distinct dysbiotic signatures that foster resistance through direct drug inactivation, biofilm formation, metabolite-mediated immune suppression, and activation of oncogenic signaling pathways. At the same time, PDAC cells undergo metabolic reprogramming, including enhanced glycolysis, glutamine dependence, and altered amino acid and nucleotide metabolism. These changes create a nutrient environment that may favor the colonization of pro-resistance microbes and further reinforce therapy resistance. In this review, we integrate evidence across the oral-gut-pancreas axis to clarify how microbiome dysbiosis and host metabolic rewiring converge to promote drug resistance, remodel the tumor microenvironment (TME), and reveal therapeutic vulnerabilities in PDAC. Targeting selected components of this crosstalk through precision antibiotics, fecal microbiota transplantation (FMT), metabolic enzyme inhibitors, and rational combination strategies may offer therapeutic opportunities. However, interindividual variability and mechanistic complexity pose significant barriers. Integrating multi-omics, artificial intelligence, and personalized medicine may help decode microbial-metabolic signatures and support more precise strategies to overcome resistance and improve clinical outcomes in PDAC.