The Interplay Between DNA Repair and the Immune Microenvironment in Pancreatic Cancer

This narrative review describes the relationship between DNA repair and the immune microenvironment in pancreatic cancer and its potential clinical relevance. Pancreatic cancer is a devastating disease, often diagnosed at an advanced and incurable stage. BRCA or PALB2 mutations occur in a small subset, disabling accurate DNA double-strand break repair and sensitizing tumors to platinum-based chemotherapy and poly-ADP ribose polymerase inhibitors. While immune checkpoint blockade targeting PD1 and CTLA4 is ineffective for most patients, accumulating translational work indicates that those with BRCA or PALB2 mutations harbor a distinct and more permissive immune microenvironment. The phase 2 TAPUR study and retrospective series demonstrate that combined PD1 and CTLA4 inhibition can be effective for this subgroup of patients. In this manuscript, we review the current treatment landscape, the underlying mechanisms for immune resistance, and the interplay between defective DNA repair and the immune microenvironment in pancreatic cancer.