The tumor microenvironment in pancreatic cancer: from composition to therapeutic targeting

Pancreatic cancer, predominantly represented by Pancreatic Ductal Adenocarcinoma (PDAC), is one of the most frequent and deadly types of cancer. In contrast with other types of cancer, for which advances in prevention, early detection, and treatment have contributed to decreasing incidence and mortality, PDAC continues to be rarely diagnosed at early stages of the disease and exhibits a poor prognosis. As a consequence, therapeutic efficacy remains limited, which is reflected in high mortality. Therefore, the development of novel and effective therapeutic strategies against PDAC is urgent. However, a major component limiting therapeutic efficacy is the highly complex PDAC tumor microenvironment (TME), which is composed of cancer-associated fibroblasts, immunosuppressive cells, cancer stem cells, and a dense extracellular matrix, a structural and biochemical scaffold that sustains tumor development and influences several PDAC phenotypes including metabolism, immune infiltration, metastasis, and therapeutic response. The present review focuses on and discusses the key components of the PDAC TME, with particular emphasis on ECM remodeling, stromal components, their impact on tumor progression and therapeutic resistance, and emerging strategies to target these processes.