免疫细胞上的共刺激受体对于免疫治疗具有吸引力，因为这些分子能够增加个体保护性免疫细胞群体的频率和寿命，以及增强各种效应器功能。4-1BB是TNF受体超家族的成员，也被称为CD137和TNFRSF9，是一种在包括T细胞和NK细胞在内的几种细胞类型上可诱导的分子。动物模型中的临床前研究证实了刺激4-1BB与激动剂试剂或其天然配体，可以增强传统T细胞和NK细胞免疫以保护免受肿瘤生长和病毒感染的概念。此外，刺激4-1BB还可以增强调节性T细胞的功能，在适当的情况下可能有益于抑制自身免疫。已经生产并在癌症临床试验中测试了两种针对4-1BB的人类激动剂抗体，结果有所不同，导致大量第二代抗体构建物的生产，包括双特异性和多特异性，希望能够优化活性和选择性。在这里，我们回顾了迄今为止在4-1BB激动剂方面取得的进展，讨论了在适当地靶向免疫系统以引发所需活性方面的复杂问题，以及在工程化激动剂方面面临的挑战，并强调了在传染病和自身免疫中操纵该分子的潜在潜力。版权所有 © 2023 Salek-Ardakani, Zajonc, 和 Croft.

Costimulatory receptors on immune cells represent attractive targets for immunotherapy given that these molecules can increase the frequency of individual protective immune cell populations and their longevity, as well as enhance various effector functions. 4-1BB, a member of the TNF receptor superfamily, also known as CD137 and TNFRSF9, is one such molecule that is inducible on several cell types, including T cells and NK cells. Preclinical studies in animal models have validated the notion that stimulating 4-1BB with agonist reagents or its natural ligand could be useful to augment conventional T cell and NK cell immunity to protect against tumor growth and against viral infection. Additionally, stimulating 4-1BB can enhance regulatory T cell function and might be useful in the right context for suppressing autoimmunity. Two human agonist antibodies to 4-1BB have been produced and tested in clinical trials for cancer, with variable results, leading to the production of a wealth of second-generation antibody constructs, including bi- and multi-specifics, with the hope of optimizing activity and selectivity. Here, we review the progress to date in agonism of 4-1BB, discuss the complications in targeting the immune system appropriately to elicit the desired activity, together with challenges in engineering agonists, and highlight the untapped potential of manipulating this molecule in infectious disease and autoimmunity.Copyright © 2023 Salek-Ardakani, Zajonc and Croft.