Overcoming the Fibrotic Fortress in Pancreatic Ductal Adenocarcinoma: Challenges and Opportunities

Simple Summary Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic tumours, representing greater than 90% of all diagnosed cases of pancreatic cancer. PDAC has the lowest 5-year survival rate of all tumour malignancies with less than 9% patient survival. A unique feature of PDAC tumours is the presence of a dense fibrotic fortress that creates a physical barrier around the cancer cells, thus resulting in a reduced penetrability of drugs and a 'sanctuary' in which cancer cells thrive, termed desmoplasia. Extensive desmoplasia in the PDAC tumour microenvironment (TME) is a crucial factor that influences PDAC development, progression, metastasis, and resistance to treatment. This review will focus on the role of the TME in PDAC, current treatments for PDAC, and a reflection on past and current clinical trials targeting components of the TME in PDAC. An overabundance of desmoplasia in the tumour microenvironment (TME) is one of the defining features that influences pancreatic ductal adenocarcinoma (PDAC) development, progression, metastasis, and treatment resistance. Desmoplasia is characterised by the recruitment and activation of fibroblasts, heightened extracellular matrix deposition (ECM) and reduced blood supply, as well as increased inflammation through an influx of inflammatory cells and cytokines, creating an intrinsically immunosuppressive TME with low immunogenic potential. Herein, we review the development of PDAC, the drivers that initiate and/or sustain the progression of the disease and the complex and interwoven nature of the cellular and acellular components that come together to make PDAC one of the most aggressive and difficult to treat cancers. We review the challenges in delivering drugs into the fortress of PDAC tumours in concentrations that are therapeutic due to the presence of a highly fibrotic and immunosuppressive TME. Taken together, we present further support for continued/renewed efforts focusing on aspects of the extremely dense and complex TME of PDAC to improve the efficacy of therapy for better patient outcomes.