Department of Oncology, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610054, China.
Institute for Breast Health Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
Cancer Biol Med. 2024 May 9;21(5):382-99. doi: 10.20892/j.issn.2095-3941.2024.0034.
Immune checkpoint inhibitors (ICIs) are used to relieve and refuel anti-tumor immunity by blocking the interaction, transcription, and translation of co-inhibitory immune checkpoints or degrading co-inhibitory immune checkpoints. Thousands of small molecule drugs or biological materials, especially antibody-based ICIs, are actively being studied and antibodies are currently widely used. Limitations, such as anti-tumor efficacy, poor membrane permeability, and unneglected tolerance issues of antibody-based ICIs, remain evident but are thought to be overcome by small molecule drugs. Recent structural studies have broadened the scope of candidate immune checkpoint molecules, as well as innovative chemical inhibitors. By way of comparison, small molecule drug-based ICIs represent superior oral bioavailability and favorable pharmacokinetic features. Several ongoing clinical trials are exploring the synergetic effect of ICIs and other therapeutic strategies based on multiple ICI functions, including immune regulation, anti-angiogenesis, and cell cycle regulation. In this review we summarized the current progression of small molecule ICIs and the mechanism underlying immune checkpoint proteins, which will lay the foundation for further exploration.
免疫检查点抑制剂（ICIs）通过阻断共抑制免疫检查点的相互作用、转录和翻译或降解共抑制免疫检查点来缓解和增强抗肿瘤免疫。成千上万的小分子药物或生物材料，特别是基于抗体的 ICIs，正在积极研究中，并且抗体目前被广泛应用。基于抗体的 ICIs 的局限性，如抗肿瘤疗效、较差的膜通透性和被忽视的耐受性问题仍然很明显，但人们认为小分子药物可以克服这些问题。最近的结构研究拓宽了候选免疫检查点分子的范围，以及创新的化学抑制剂。相比之下，基于小分子药物的 ICIs 具有更好的口服生物利用度和良好的药代动力学特征。目前正在进行几项临床试验，以探索基于多种 ICI 功能（包括免疫调节、抗血管生成和细胞周期调节）的 ICIs 和其他治疗策略的协同作用。在这篇综述中，我们总结了小分子 ICIs 的最新进展和免疫检查点蛋白的作用机制，为进一步探索奠定了基础。
