Intratumoral microbiome and pancreatic cancer: an enabling hallmark and path to novel treatments?

In 2022, Hanahan integrated polymorphic microbiomes to the hallmarks of cancer, resulting in 14 overarching features that are considered fundamental to initiation and progression of cancers. It is well acknowledged that genomic instability/genetic alterations together with tumor-associated inflammation are so called "enabling hallmarks" as they drive the acquisition of the other traits. The microbiome is a key component of the inflammatory tumor stroma. Pancreatic ductal adenocarcinoma (PDAC) in particular is characterized by a pronounced stromal compartment whose role in the acquisition of malignant properties is well documented. Recent studies indicate massive alterations of the microbiome in PDAC tissues compared to healthy pancreas or precursor lesions. However, the mechanistic role of the PDAC-associated microbiome, its influence on the hallmarks of cancer, and how this relates to PDAC malignancy remain poorly understood. This raises the question of whether the tumor-associated microbiome through its direct influence on PDAC cells, their precursors, and the surrounding non-neoplastic cells promotes the acquisition of other hallmarks that drive PDAC development and progression. This perspective article outlines the current knowledge of the impact of the PDAC-associated microbiome on the hallmarks of cancer in PDAC. These current findings support the altered microbiome as a third enabling hallmark of PDAC and emphasize that further mechanistic studies are urgently needed to further substantiate its fundamental importance for this tumor entity. This knowledge will provide the basis for clinical translation to develop more effective therapeutic approaches for PDAC. The intratumoral microbiome in PDAC exhibits numerous interactions with the hallmarks of cancer. Hallmarks indicated in blue have demonstrated interactions with the microbiome, while others still remain underexplored. These extensive interactions substantiate the role of the intratumoral microbiome in PDAC as an enabling hallmark, underlining its potential as a therapeutic target. Partially created with biorender.com.