Pancreatic cancer is resistant to the immunotherapy. This resistance is caused by any of the four immune "defects" that occur in pancreatic cancer, including lack of "high quality" T cells, stromal barriers to T cells getting access to tumor cells, immunosuppressive cells such as M2 macrophages, myeloid derivative suppressor cells, and T regulatory cells, in the tumor microenvironment of pancreatic cancer. One or more defects may occur in an individual pancreatic cancer. To overcome the resistance to the immunotherapy such as immune checkpoint inhibitors, a rational combination of agents that target multiple immune defects is highly demanded.