Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China.
Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), PR China; Institute of Cancer and Basic Medicine (IBMC), Chinese Academy of Sciences, PR China.
Eur J Med Chem. 2021 Jun 5;218:113356. doi: 10.1016/j.ejmech.2021.113356. Epub 2021 Mar 11.
Anti-cancer immunotherapy, which includes cellular immunotherapy, immune checkpoint inhibitors and cancer vaccines, has transformed the treatment strategies of several malignancies in the past decades. Immune checkpoints blockade (ICB) is the most commonly tested therapy and has the potential to induce a durable immune response in different types of cancers. However, all approved immune checkpoint inhibitors (ICIs) are monoclonal antibodies (mAbs), which are fraught with disadvantages including lack of oral bioavailability, prolonged tissue retention and poor membrane permeability. Therefore, the research focus has shifted to developing small molecule inhibitors to obviate the limitations of mAbs. Given the complexity of the tumor micro-environment (TME), the combination of ICIs with various small molecule agonists/inhibitors are currently being tested in clinical trials to improve treatment outcomes and prevent tumor recurrence. In this review, we have summarized the mechanisms and therapeutic potential of several molecular targets, along with the current status of small molecule inhibitors.
在过去几十年中，癌症免疫疗法（包括细胞免疫疗法、免疫检查点抑制剂和癌症疫苗）改变了多种恶性肿瘤的治疗策略。免疫检查点阻断（ICB）是最常被测试的疗法，有可能在不同类型的癌症中诱导持久的免疫反应。然而，所有批准的免疫检查点抑制剂（ICI）都是单克隆抗体（mAbs），它们存在缺乏口服生物利用度、组织保留时间延长和膜通透性差等缺点。因此，研究重点已转向开发小分子抑制剂以避免 mAbs 的局限性。鉴于肿瘤微环境（TME）的复杂性，目前正在临床试验中测试 ICI 与各种小分子激动剂/抑制剂的联合应用，以改善治疗效果和预防肿瘤复发。在这篇综述中，我们总结了几种分子靶标的作用机制和治疗潜力，以及小分子抑制剂的现状。
