尽管抗程序性细胞死亡-1（抗PD-1）免疫疗法取得了成功，但许多癌症患者仍然没有反应，并且缺乏可靠的预测生物标志物。在这里，我们发现嘧啶能受体 P2RY6 的异常表达在人类癌症中很常见，并导致免疫逃避。在小鼠同基因和人类异种移植肿瘤模型中，P2RY6的异位表达塑造了免疫抑制肿瘤微环境（TME），以增强肿瘤生长和对免疫治疗的抵抗力，而从高P2RY6表达的肿瘤中删除P2RY6会导致TME发炎，从而抑制肿瘤生长。作为 G 蛋白偶联受体，P2RY6 激活 Gq/磷脂酶 C-β 信号传导并刺激前列腺素 E2 的合成，前列腺素 E2 是 TME 中免疫抑制的关键介质。与 P2RY6 在肿瘤中的重要作用相反，小鼠体内 P2ry6 的整体缺失不会损害生存能力。因此，我们的研究提名 P2RY6 作为肿瘤内在 P2RY6 高表达患者的精准免疫治疗靶点。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

Despite the success of anti-programmed cell death-1 (anti-PD-1) immunotherapy, many cancer patients remain unresponsive, and reliable predictive biomarkers are lacking. Here, we show that aberrant expression of the pyrimidinergic receptor P2RY6 is frequent in human cancers and causes immune evasion. In mouse syngeneic and human xenograft tumor models, ectopic expression of P2RY6 shapes an immunosuppressive tumor microenvironment (TME) to enhance tumor growth and resistance to immunotherapy, whereas deletion of P2RY6 from tumors with high P2RY6 expression inflames the TME to inhibit tumor growth. As a G protein-coupled receptor, P2RY6 activates Gq/phospholipase C-β signaling and stimulates the synthesis of prostaglandin E2, which is a key mediator of immunosuppression in the TME. In contrast to the essential role of P2RY6 in tumors, global deletion of P2ry6 from mice does not compromise viability. Our study thus nominates P2RY6 as a precision immunotherapy target for patients with high tumor-intrinsic P2RY6 expression.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.