基于 PD-1 和 CTLA-4 免疫检查点阻断 (ICB) 的癌症免疫疗法的出现彻底改变了癌症治疗。然而，许多癌症对 ICB 没有反应，这凸显了迫切需要其他方法来实现持久的癌症缓解。 G 蛋白偶联受体 (GPCR) 大家族是所有已批准药物中超过 30% 的靶标，但 GPCR 在癌症免疫治疗中尚未得到充分利用。在这篇综述中，我们讨论了 GPCR 在免疫细胞迁移和功能中的核心作用，并描述了单细胞转录组研究如何阐明人类肿瘤免疫 GPCRome 的复杂性。这些受体包括在 CD8 T 细胞中表达的多种 GPCR，这些受体被肿瘤微环境中积累的炎症介质、质子、神经递质和代谢物激活，从而促进 T 细胞功能障碍。我们还讨论了以 GPCR 为目标的新机会，作为一种多模式方法，以增强对多种人类恶性肿瘤的 ICB 反应。

The advent of cancer immunotherapy based on PD-1 and CTLA-4 immune checkpoint blockade (ICB) has revolutionized cancer treatment. However, many cancers do not respond to ICB, highlighting the urgent need for additional approaches to achieve durable cancer remission. The large family of G protein-coupled receptors (GPCRs) is the target of more than 30% of all approved drugs, but GPCRs have been underexploited in cancer immunotherapy. In this review, we discuss the central role of GPCRs in immune cell migration and function and describe how single-cell transcriptomic studies are illuminating the complexity of the human tumor immune GPCRome. These receptors include multiple GPCRs expressed in CD8 T cells that are activated by inflammatory mediators, protons, neurotransmitters, and metabolites that accumulate in the tumor microenvironment, thereby promoting T cell dysfunction. We also discuss new opportunities to target GPCRs as a multimodal approach to enhance the response to ICB for a myriad of human malignancies.