1 型先天淋巴细胞 (ILC1) 是一类具有抗肿瘤活性的组织驻留细胞，表明其可能在实体瘤免疫监视中发挥作用，但尚不清楚操纵 ILC1 是否可以诱导有效的抗肿瘤免疫反应。在这里，我们发现 G 蛋白偶联受体 34 (GPR34)，一种溶血磷脂酰丝氨酸 (LysoPS) 受体，在 ILC1 上高表达，但在肿瘤微环境中的传统自然杀伤细胞上不表达。 LysoPS 在肿瘤微环境中富集，可以通过 GPR34 抑制 ILC1 激活。肿瘤中 LysoPS 合酶 Abhd16a 表达的基因缺失或 ILC1 中 Gpr34 表达的基因缺失或拮抗 GPR34 增强了 ILC1 的抗肿瘤活性。在癌症个体中，肿瘤中的 ABHD16A 表达或 ILC1 中的 GPR34 表达与 ILC1 或 ILC1 样细胞的抗肿瘤活性呈负相关。因此，我们的结果表明，操纵 ILC1 可以诱导有效的抗肿瘤免疫，而 GPR34 是一种代谢免疫检查点，可以靶向开发基于 ILC1 的免疫疗法。© 2024。作者，获得 Springer Nature America, Inc 的独家许可。

Type 1 innate lymphoid cells (ILC1s) are a class of tissue-resident cells with antitumor activity, suggesting its possible role in solid tumor immune surveillance, but it is not clear whether manipulating ILC1s can induce potent antitumor immune responses. Here, we found that G-protein-coupled receptor 34 (GPR34), a receptor for lysophosphatidylserine (LysoPS), was highly expressed on ILC1s but not on conventional natural killer cells in the tumor microenvironment. LysoPS was enriched in the tumor microenvironment and could inhibit ILC1 activation via GPR34. Genetic deletion of LysoPS synthase Abhd16a expression in tumors or Gpr34 expression in ILC1s or antagonizing GPR34 enhanced ILC1 antitumor activity. In individuals with cancer, ABHD16A expression in tumors or GPR34 expression in ILC1s was inversely correlated with the antitumor activity of ILC1s or ILC1-like cells. Thus, our results demonstrate that manipulating ILC1s can induce potent antitumor immunity, and GPR34 is a metabolic immune checkpoint that can be targeted to develop ILC1-based immunotherapy.© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.