CD137 激动性抗体已被证明可以通过激活 T 细胞免疫来完全消退已形成的肿瘤。不幸的是，目前的 CD137 抗体未能使癌症患者受益。此外，它们的体内抗肿瘤机制仍有待确定。在这里，我们报告了小分子 CD137 激动剂 JNU-0921 的开发。 JNU-0921通过直接结合人类和小鼠CD137的细胞外结构域，有效激活它们，诱导寡聚化和信号传导，并有效缩小体内肿瘤。从机制上讲，JNU-0921 增强细胞毒性 CD8 T 细胞 (CTL) 的效应器和记忆功能，并减轻其耗竭。 JNU-0921 还会使辅助 T 细胞偏向 T 辅助 1 型，并增强其活性以增强 CTL 功能。同时，JNU-0921 减弱调节性 T 细胞对 CTL 的抑制功能。我们目前的工作表明，JNU-0921 通过增强顺式和反式 CTL 的细胞毒性来缩小肿瘤，并为开发 CD137 小分子激动剂的策略提供了线索。

Agonistic antibodies against CD137 have been demonstrated to completely regress established tumors through activating T cell immunity. Unfortunately, current CD137 antibodies failed to benefit patients with cancer. Moreover, their antitumor mechanisms in vivo remain to be determined. Here, we report the development of a small molecular CD137 agonist, JNU-0921. JNU-0921 effectively activates both human and mouse CD137 through direct binding their extracellular domains to induce oligomerization and signaling and effectively shrinks tumors in vivo. Mechanistically, JNU-0921 enhances effector and memory function of cytotoxic CD8+ T cells (CTLs) and alleviates their exhaustion. JNU-0921 also skews polarization of helper T cells toward T helper 1 type and enhances their activity to boost CTL function. Meanwhile, JNU-0921 attenuates the inhibitory function of regulatory T cells on CTLs. Our current work shows that JNU-0921 shrinks tumors by enhancing the cytotoxicity of CTLs in cis and in trans and sheds light on strategy for developing CD137 small molecular agonists.