Simple SummaryThe aim of this review was to gather a deeper insight on the mechanisms of Pancreatic Ductal Adenocarcinoma (PDAC), with a particular focus on its biomolecular variety and underlying intracellular and intercellular mechanisms. This was obtained through a critical approach to the current literature on PDAC. We were astounded by the dramatic role played by the Tumoral Microenvironment (TME) in the natural history of this disease, as well as its complexity, which stems from the combination of cellular and acellular components. This, in turn, led us to shift our attention to the current state of PDAC therapy, which at present relies heavily on traditional, invasive techniques. However, recent discoveries such as CAR-T and hyaluronidase-based protocols, give us hope that future approaches will be tailored around each patient’s needs for a better clinical outcome.AbstractPancreatic ductal adenocarcinoma (PDAC) is among the leading causes of death by cancer in the world. What makes this pathological condition particularly lethal is a combination of clinical and molecular heterogeneity, lack of early diagnostic indexes, and underwhelming results from current therapeutic protocols. A major cause of PDAC chemoresistance seems to lie in the ability of cancer cells to spread out and fill the pancreatic parenchyma, exchanging nutrients, substrates, and even genetic material with cells from the surrounding tumor microenvironment (TME). Several components can be found in the TME ultrastructure, including collagen fibers, cancer-associated fibroblasts, macrophages, neutrophils, mast cells, and lymphocytes. Cross-talk between PDAC and TME cells results in the latter being converted into cancer-favoring phenotypes; this behavior could be compared to an influencer guiding followers into supporting his activity. Moreover, TME could be a potential target for some of the newest therapeutic strategies; these include the use of pegvorhyaluronidase-α and CAR-T lymphocytes against HER2, FAP, CEA, MLSN, PSCA, and CD133. Other experimental therapy options are being currently studied, aiming to interfere with the KRAS pathway, DNA-repairing proteins, and apoptosis resistance in PDAC cells. Hopefully these new approaches will grant better clinical outcomes in future patients.