Cheng Binbin, Lv Jinke, Xiao Yao, Song Changshan, Chen Jianjun, Shao Chuxiao
Central Laboratory, Wenzhou Medical University Lishui Hospital, Lishui People's Hospital, Lishui, Zhejiang 323000, China; Hubei Polytechnic University, Huangshi, Hubei 435003, China.
Foshan Clinical Medical School of Guangzhou University of Chinese Medicine, Foshan 528000, China.
Eur J Med Chem. 2025 Feb 5;283:117141. doi: 10.1016/j.ejmech.2024.117141. Epub 2024 Dec 5.
Cancer immunotherapy, leveraging antibodies, excels in targeting efficacy but faces hurdles in tissue penetration, oral delivery, and prolonged half-life, with costly production and risk of adverse immunogenic effects. In contrast, small molecule immuno-oncology agents provide favorable pharmacokinetic properties and benign toxicity profiles. These agents are well-positioned to address the limitations of antibody-based immunotherapies, augment existing treatment modalities, and achieve synergistic effects when combined with antibodies. This review, for the first time, summarizes the recent advances (2020-2024) in small molecule inhibitors targeting PD-1/PD-L1, CTLA4, VISTA, TIM-3, and LAG3, highlighting rational design, benefits, and potential limitations. It also outlines the prospects for small-molecule immunotherapy.
癌症免疫疗法利用抗体，在靶向疗效方面表现出色，但在组织渗透、口服给药和延长半衰期方面面临障碍，且生产成本高昂，还存在产生不良免疫原性效应的风险。相比之下，小分子免疫肿瘤药物具有良好的药代动力学特性和良性毒性特征。这些药物能够很好地解决基于抗体的免疫疗法的局限性，增强现有治疗方式，并在与抗体联合使用时产生协同效应。本综述首次总结了2020年至2024年期间靶向PD-1/PD-L1、CTLA4、VISTA、TIM-3和LAG3的小分子抑制剂的最新进展，重点介绍了合理设计、优势和潜在局限性。此外，还概述了小分子免疫疗法的前景。
