Loss of MED12 Enhances Immunotherapy Response in Pancreatic Cancer via Retroelement Activation

A recent study published in Gut identifies MED12 as a critical negative regulator of immune activation in pancreatic ductal adenocarcinoma (PDAC). Using an epigenetic-focused CRISPR-Cas9 screen in mouse models, researchers discovered that loss of MED12 activates previously silenced endogenous retroelements, triggering cytosolic nucleic acid sensing and type I interferon responses, thereby creating an inflamed and immunologically active tumor microenvironment. This heightened immune response increased tumor infiltration by cytotoxic immune cells, significantly enhancing sensitivity to checkpoint blockade immunotherapy. MED12 expression levels inversely correlated with immune activity and patient prognosis, highlighting MED12 inhibition as a promising strategy to overcome immunotherapy resistance in PDAC.