P2RY6 is a G protein-coupled receptor that functions as a pyrimidine nucleotide sensor, primarily responding to extracellular UDP with lower affinity for UTP and ATP. Upon ligand binding, P2RY6 activates Gq/phospholipase C-β signaling to stimulate inositol trisphosphate production and calcium mobilization 1. Beyond canonical purinergic signaling, P2RY6 has emerged as a critical mediator in pathological inflammation and cancer immunity. In atherosclerosis, P2RY6 acts as an endogenous ceramide receptor on endothelial cells and macrophages, triggering NLRP3 inflammasome activation that aggravates disease; genetic or pharmacologic P2RY6 inhibition alleviates atherosclerosis progression 2. In cancer, P2RY6 expression is elevated across multiple malignancies including lung adenocarcinoma and pancreatic ductal adenocarcinoma, correlating with poor prognosis 34. Tumor-intrinsic P2RY6 drives immunosuppression by enhancing prostaglandin E2 synthesis, creating an immunosuppressive microenvironment that promotes immune checkpoint inhibitor resistance 1. Cancer cells exploit P2RY6 on tumor-associated macrophages through UDP signaling to establish immunosuppressive crosstalk that blocks anti-PD-1 responses 5. P2RY6 expression is transcriptionally regulated by p53 status in inflammatory bowel disease and colorectal cancer contexts 6. These findings establish P2RY6 as a therapeutic target for cardiovascular and oncological diseases.