Cancer-associated fibroblasts (CAFs) represent an abundant and heterogeneous component of pancreatic ductal adenocarcinoma (PDAC) but their interplay with natural killer (NK) cells is largely understudied. Rodrigues et al. show that CAFs, particularly myofibroblastic (my)CAF modulate NK anti-tumor capacity. This is mediated partially by prostaglandin E2, affecting granzyme B expression.