The development of immune checkpoint inhibitors has become a research hotspot in cancer immunotherapy in recent years. Anti-PD-1/PD-L1 monoclonal antibodies (mAbs), such as pembrolizumab and nivolumab have been approved for treating different types of cancer. Many peptides, peptidomimetics and non-peptide small-molecule inhibitors targeting the PD-1/PD-L1 axis have been published so far. In comparison with mAbs, small-molecule inhibitors have the potential to overcome inherent shortcomings of mAbs, such as poor oral bioavailability, low tumor penetration, and high manufacturing costs. In this article, we mainly review non-peptide small-molecule inhibitors of the PD-1/PD-L1 interaction, their cocrystal structures, docking studies, and biological activities are also included to guide future study. In addition, we propose several strategies for designing more effective small-molecule modulators of the PD-1/PD-L1 pathway.

近年来，免疫检查点抑制剂的开发成为癌症免疫治疗的研究热点。抗 PD-1/PD-L1 单克隆抗体 (mAb)，例如派姆单抗和纳武单抗，已被批准用于治疗不同类型的癌症。迄今为止，已经发表了许多针对 PD-1/PD-L1 轴的肽、肽模拟物和非肽小分子抑制剂。与 mAb 相比，小分子抑制剂有可能克服 mAb 固有的缺点，例如口服生物利用度差、肿瘤渗透率低和制造成本高。在本文中，我们主要回顾了 PD-1/PD-L1 相互作用的非肽类小分子抑制剂、它们的共晶结构、对接研究和生物学活性，以指导未来的研究。此外，