A Review on Microbial Strategies to Combat Chemoresistance in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) stands as one of the most lethal forms of cancer, characterized by a dismal prognosis and a marked resistance to conventional chemotherapeutic interventions, particularly gemcitabine. Despite advances in targeted therapies and immune modulation, the survival rate for PDAC remains under 10% due to late-stage diagnosis, dense desmoplastic stroma, and immunosuppressive tumor microenvironment. Recent insights into the role of microorganisms, both endogenous and engineered—have opened new avenues in understanding and potentially reversing chemoresistance. Microbes, including certain classes of intratumoral bacteria such as Gammaproteobacteria, have been shown to enzymatically degrade chemotherapeutic drugs, reducing their efficacy. Conversely, the exploitation of these microbial communities offers novel therapeutic approaches: genetically modified bacteria and oncolytic viruses are capable of selectively targeting tumors, modulating immune responses, and enhancing drug bioavailability. Furthermore, strategies such as fecal microbiota transplantation (FMT), probiotic therapy, and microbial metabolite supplementation are being explored to improve patient responses and restore immune competence. This review explores the complex and dualistic relationship between the microbiome and PDAC, detailing the mechanisms of microbial-mediated chemoresistance, the therapeutic potential of microbial engineering, and the challenges inherent in clinical translation. Through a synthesis of recent literature and clinical studies, we propose a future in which microbiome-targeted therapies play a pivotal role in combating pancreatic cancer and improving patient outcomes.