The PD-1 pathway is a cornerstone in immune regulation. While the PD-1 pathway has received considerable attention for its role in contributing to the maintenance of T cell exhaustion in chronic infection and cancer, the PD-1 pathway plays diverse roles in regulating host immunity beyond T cell exhaustion. Here, we discuss emerging concepts in the PD-1 pathway, including (1) the impact of PD-1 inhibitors on diverse T cell differentiation states including effector and memory T cell development during acute infection, as well as T cell exhaustion during chronic infection and cancer, (2) the role of PD-1 in regulating Treg cells, NK cells, and ILCs, and (3) the functions of PD-L1/B7-1 and PD-L2/RGMb/neogenin interactions. We then discuss the emerging use of neoadjuvant PD-1 blockade in the treatment of early-stage cancers and how the timing of PD-1 blockade may improve clinical outcomes. The diverse binding partners of PD-1 and its associated ligands, broad expression patterns of the receptors and ligands, differential impact of PD-1 modulation on cells depending on location and state of differentiation, and timing of PD-1 blockade add additional layers of complexity to the PD-1 pathway, and are important considerations for improving the efficacy and safety of PD-1 pathway therapeutics.

PD-1 通路是免疫调节的基石。虽然 PD-1 通路因其在慢性感染和癌症中维持 T 细胞耗竭的作用而受到相当多的关注，但除了 T 细胞耗竭之外，PD-1 通路在调节宿主免疫方面也发挥着多种作用。在这里，我们讨论 PD-1 通路中的新兴概念，包括 (1) PD-1 抑制剂对不同 T 细胞分化状态的影响，包括急性感染期间效应和记忆 T 细胞的发育，以及慢性感染期间 T 细胞耗竭和癌症，(2) PD-1 在调节 Treg 细胞、NK 细胞和 ILC 中的作用，以及 (3) PD-L1/B7-1 和 PD-L2/RGMb/neogenin 相互作用的功能。然后，我们讨论新辅助 PD-1 阻断在治疗早期癌症中的新应用，以及 PD-1 阻断的时机如何改善临床结果。PD-1 及其相关配体的多种结合伴侣、受体和配体的广泛表达模式、PD-1 调节对细胞的不同影响（取决于分化的位置和状态）以及 PD-1 阻断的时间增加了额外的层PD-1 通路的复杂性，是提高 PD-1 通路治疗的疗效和安全性的重要考虑因素。