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Microbiome dysbiosis and KRAS-driven tumorigenesis in pancreatic cancer: implications for immune checkpoint inhibitors efficacy
Giulia Massaro (Azienda Ospedaliero-Universitaria Careggi), Daniele Lavacchi (Azienda Ospedaliero-Universitaria Careggi), Tommaso Innocenti (University of Florence), Simone Polvani (University of Florence), Andrea Galli (University of Florence), Antonio Taddei (University of Florence), Giulia Petroni (University of Florence), Daniele Rossini (Azienda Ospedaliero-Universitaria Careggi, University of Florence), Serena Pillozzi (University of Florence), Lorenzo Antonuzzo (Azienda Ospedaliero-Universitaria Careggi, University of Florence)
Abstract: Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related deaths due to its late diagnosis, limited treatment options, and early metastasis, resulting in a five-year survival rate of less than 10 %. Central to PDAC development are mutations in the KRAS gene, which drive tumor growth through persistent activation of signaling pathways. The microbiota, comprising bacteria, viruses, and fungi, plays a vital role in human health by aiding digestion, supporting immune function, and maintaining microbial balance. Dysbiosis, an imbalance in microbial communities, is linked to various diseases. Recent research highlights the complex interaction between the pancreas and gut microbiota, with evidence suggesting that microbiota influences pancreatic functions, including enzyme secretion and glucose regulation. This review focuses on the role of microbiome dysbiosis in PDAC, influencing tumorigenesis, immune response, and treatment outcomes through complex interactions with genetic mutations and metabolic pathways, and on the role of the microbiota in influencing KRAS -driven tumorigenesis, where dysbiosis may promote tumor progression. This review also aims to emphasize how the gut microbiome has been implicated in modulating the response to immune checkpoint inhibitors (ICIs) across various cancers, with specific bacterial strains linked to improved outcomes. Recent studies suggest that microbial manipulation, such as bacterial ablation, can enhance anti-tumor immunity in PDAC models by altering the tumor microenvironment (TME). The TME remains a major barrier, and ongoing research is exploring new combinations and targets to overcome resistance and improve the efficacy of ICIs in PDAC. Further research is needed to fully understand this relationship.