NK cells are critical innate immune cells that target the tumor cells and cancer-initiating cells and clear viruses by producing cytokines and cytotoxic granules. However, the role of the purinergic receptor P2Y₆ in the NK cells remains largely unknown. In this study, we discovered that the expression of P2Y₆ was decreased upon the activation of the NK cells. Moreover, in the P2Y₆-deficient mice, we found that the deficiency of P2Y₆ promoted the development of the NK precursor cells into immature NK and mature NK cells. We also found that the P2Y₆ deficiency increased, but the P2Y₆ receptor agonist UDP or UDP analog 5-OMe-UDP decreased the production of IFN-γ in the activated NK cells. Furthermore, we demonstrated that the P2Y₆-deficient NK cells exhibited stronger cytotoxicity in vitro and antimetastatic effects in vivo. Mechanistically, P2Y₆ deletion promoted the expression of T-bet (encoded by Tbx21), with or without the stimulation of IL-15. In the absence of P2Y₆, the levels of phospho-serine/threonine kinase and pS6 in the NK cells were significantly increased upon the stimulation of IL-15. Collectively, we demonstrated that the P2Y₆ receptor acted as a negative regulator of the NK cell function and inhibited the maturation and antitumor activities of the NK cells. Therefore, inhibition of the P2Y₆ receptor increases the antitumor activities of the NK cells, which may aid in the design of innovative strategies to improve NK cell–based cancer therapy.

NK 细胞是关键的先天免疫细胞，通过产生细胞因子和细胞毒性颗粒来靶向肿瘤细胞和癌症起始细胞并清除病毒。然而，嘌呤能受体 P2Y ₆在 NK 细胞中的作用仍然未知。在这项研究中，我们发现 P2Y ₆的表达在 NK 细胞活化后降低。此外，在 P2Y ₆缺陷小鼠中，我们发现 P2Y ₆缺陷促进了 NK 前体细胞向未成熟 NK 和成熟 NK 细胞的发育。我们还发现 P2Y ₆缺乏增加，但 P2Y ₆受体激动剂 UDP 或 UDP 类似物 5-OMe-UDP 减少了活化 NK 细胞中 IFN-γ 的产生。此外，我们证明了 P2Y ₆缺陷型 NK 细胞在体外表现出更强的细胞毒性和体内抗转移作用。从机制上讲，无论是否有 IL-15 的刺激，P2Y ₆缺失都会促进 T-bet（由 Tbx21 编码）的表达。在不存在 P2Y ₆的情况下，NK 细胞中磷酸丝氨酸/苏氨酸激酶和 pS6 的水平在 IL-15 的刺激下显着增加。总的来说，我们证明了 P2Y ₆受体作为 NK 细胞功能的负调节剂，并抑制了 NK 细胞的成熟和抗肿瘤活性。因此，抑制 P2Y₆受体增加了 NK 细胞的抗肿瘤活性，这可能有助于设计创新策略以改进基于 NK 细胞的癌症治疗。