[Why is pancreatic adenocarcinoma resistant to immunotherapy?]

Immunotherapy, particularly immune checkpoint inhibitors (ICI), has revolutionized cancer treatment but remains largely ineffective in pancreatic adenocarcinoma. This resistance is due to the tumor's complex microenvironment and low immunogenicity. ICI have shown benefits only in rare MSI-High or dMMR tumors. Combining ICI with chemotherapy has not significantly improved survival outcomes. Pancreatic adenocarcinoma is considered a "cold" tumor with few neoantigens and a dense, immunosuppressive stromal component. Cancer-associated fibroblasts and myeloid cells play a key role in immune escape. Targeting the tumor microenvironment, especially through CD40 activation, has shown promising results. Personalized cancer vaccines targeting specific or shared neoantigens are emerging and show encouraging potential.