The discovery and clinical implementation of immune-checkpoint inhibitors (ICIs) targeting CTLA4, PD-1 and PD-L1 has revolutionized the treatment of cancer, as recognized by the 2018 Nobel Prize for Medicine and Physiology. This groundbreaking new approach has improved the outcomes of patients with various forms of advanced-stage cancer; however, the majority of patients receiving these therapies, even in combination, do not derive clinical benefit. Further development of agents targeting additional immune checkpoints, co-stimulatory receptors and/or co-inhibitory receptors that control T cell function is therefore critical. In this Review, we discuss the translational potential and clinical development of agents targeting both co-stimulatory and co-inhibitory T cell receptors. Specifically, we describe their mechanisms of action, and provide an overview of ongoing clinical trials involving novel ICIs including those targeting LAG3, TIM3, TIGIT and BTLA as well as agonists of the co-stimulatory receptors GITR, OX40, 41BB and ICOS. We also discuss several additional approaches, such as harnessing T cell metabolism, in particular via adenosine signalling, inhibition of IDO1, and targeting changes in glucose and fatty acid metabolism. We conclude that further efforts are needed to optimize the timing of combination ICI approaches and, most importantly, to individualize immunotherapy based on both patient-specific and tumour-specific characteristics.

靶向 CTLA4、PD-1 和 PD-L1 的免疫检查点抑制剂 (ICI) 的发现和临床实施彻底改变了癌症的治疗方法，获得了 2018 年诺贝尔医学和生理学奖。这种开创性的新方法改善了各种形式的晚期癌症患者的预后；然而，大多数接受这些疗法的患者，即使是联合疗法，也没有获得临床益处。因此，进一步开发靶向控制 T 细胞功能的额外免疫检查点、共刺激受体和/或共抑制受体的药物至关重要。在这篇综述中，我们讨论了靶向共刺激和共抑制 T 细胞受体的药物的转化潜力和临床开发。具体来说，我们描述了它们的作用机制，并概述正在进行的涉及新型 ICI 的临床试验，包括靶向 LAG3、TIM3、TIGIT 和 BTLA 以及共刺激受体 GITR、OX40、41BB 和 ICOS 的激动剂。我们还讨论了其他几种方法，例如利用 T 细胞代谢，特别是通过腺苷信号传导、抑制 IDO1 以及靶向葡萄糖和脂肪酸代谢的变化。我们的结论是，需要进一步努力来优化组合 ICI 方法的时机，最重要的是，需要根据患者特异性和肿瘤特异性特征对免疫疗法进行个体化。我们还讨论了其他几种方法，例如利用 T 细胞代谢，特别是通过腺苷信号传导、抑制 IDO1 以及靶向葡萄糖和脂肪酸代谢的变化。我们的结论是，需要进一步努力来优化组合 ICI 方法的时机，最重要的是，需要根据患者特异性和肿瘤特异性特征对免疫疗法进行个体化。我们还讨论了其他几种方法，例如利用 T 细胞代谢，特别是通过腺苷信号传导、抑制 IDO1 以及靶向葡萄糖和脂肪酸代谢的变化。我们得出结论，需要进一步努力来优化组合 ICI 方法的时机，最重要的是，需要根据患者特异性和肿瘤特异性特征对免疫疗法进行个体化。