Challenges and Opportunities in Targeting the Complex Pancreatic Tumor Microenvironment.

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths with a 5-year survival rate of 13%. Surgical resection remains the only curative option as systemic therapies offer limited benefit. Poor response to chemotherapy and immunotherapy is due, in part, to the dense stroma and heterogeneous tumor microenvironment (TME). Opportunities to target the PDAC stroma may increase the effectiveness of existing or novel therapies. Current strategies targeting the stromal compartment within the PDAC TME primarily focus on degrading extracellular matrix or inhibiting stromal cell activity, angiogenesis, or hypoxic responses. In addition, extensive work has attempted to use immune targeting strategies to improve clinical outcomes. Preclinically, these strategies show promise, especially with the ability to alter the tumor ecosystem; however, when translated to the clinic, most of these trials have failed to improve overall patient outcomes. In this review, we catalog the heterogenous elements of the TME and discuss the potential of combination therapies that target the heterogeneity observed in the TME between patients and how molecular stratification could improve responses to targeted and combination therapies.