Targeting the Microenvironment to Overcome Gemcitabine Resistance in Pancreatic Cancer

Pancreatic cancer is characterized by an extensive and complex microenvironment, and is resistant to both chemotherapy and immune checkpoint blockade. The study by Principe and colleagues in this issue of Cancer Research proposes a combinatorial approach based on targeting the very mechanisms of resistance to gemcitabine, a commonly used chemotherapeutic agent. The authors show that gemcitabine treatment causes profound changes in the pancreatic cancer microenvironment, including elevated TGF beta signaling and immune checkpoint expression, as well as increased antigen presentation in tumor cells. Accordingly, they show that the combination of chemotherapy, TGF beta signaling inhibition, and immune checkpoint blockade effectively restores antitumor immunity and results in a significant survival benefit.