P2ry6, also known as the pyrimidinergic receptor P2Y6, is a G-protein-coupled receptor. It activates Gq/phospholipase C-β signaling and is involved in multiple biological pathways. P2ry6 is important in processes related to inflammation, tumorigenesis, and immune regulation [2,3,6]. Gene knockout (KO) mouse models have been crucial in studying its function.

In KO mouse models, P2ry6 deficiency alleviates ceramide-induced atherosclerosis aggravation, suggesting it has a role in the process of atherosclerosis through mediating ceramide-induced inflammasome activation [1]. In skin carcinogenesis, P2ry6-deficient mice show different responses depending on the carcinogenic factor. They are resistant to 7,12-dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin papilloma formation, while they exhibit promoted UVB-induced skin papilloma formation, indicating its complex role in skin cancer development through regulating different signaling pathways like Hippo/YAP, Wnt/β-catenin, and PI3K/AKT [3,4]. In tumor-related studies, deletion of P2ry6 from tumors with high P2ry6 expression inflames the tumor microenvironment (TME) to inhibit tumor growth, as P2ry6 in tumors enhances PGE2 production to drive immunosuppression [2]. In addition, pharmacologic or genetic inhibition of P2ry6 in tumor-associated macrophages (TAMs) disrupts TAM-mediated immunosuppression, promoting cytotoxic T cell entry and susceptibility to anti-programmed cell death protein 1 (anti-PD-1) treatment in resistant pancreatic ductal adenocarcinoma (PDAC) and melanoma models [5].

In conclusion, P2ry6 is a key player in inflammation, tumorigenesis, and immune-related processes. KO mouse models have significantly contributed to understanding its role in diseases such as atherosclerosis, skin cancer, and in the context of tumor-associated immunosuppression. These findings provide potential therapeutic targets for related diseases.