Wang Hefeng, Wu Jianhua, Fang Ying, Li Quhuan
School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China.
Int J Mol Sci. 2025 Feb 22;26(5):1903. doi: 10.3390/ijms26051903.
CD137 is a prominent costimulatory molecule of the tumor necrosis factor (TNF) receptor superfamily that activates T cells through a complex bidirectional signaling process involving CD137L. The clinical value of immunotherapies underscores the potential of CD137L/CD137 as an effective target for boosting antitumor immune responses; however, the intricate mechanisms governing these interactions have not been fully elucidated. Herein, we constructed various oligomeric states of CD137L (monomeric, dimeric, and trimeric CD137L) and explored their interactions with CD137 using molecular dynamics simulations. Our findings revealed that trimeric CD137L exhibits higher thermal stability but reduced binding affinity for CD137 compared with the dimer form, with the A'B' loop of CD137L playing a critical role in both structural stability and promoting CD137 interactions. Notably, the formation of hexameric structures enhanced the binding affinity and stability. This study provides valuable insights into the CD137L/CD137 bidirectional signaling mechanisms, which may inform the design of next-generation CD137 agonists. Ultimately, these advancements may improve cancer immunotherapy strategies, aiming to enhance therapeutic outcomes for patients through more effective and targeted therapies.
CD137是肿瘤坏死因子（TNF）受体超家族中一种重要的共刺激分子，它通过涉及CD137L的复杂双向信号传导过程激活T细胞。免疫疗法的临床价值凸显了CD137L/CD137作为增强抗肿瘤免疫反应的有效靶点的潜力；然而，这些相互作用的复杂机制尚未完全阐明。在此，我们构建了CD137L的各种寡聚状态（单体、二聚体和三聚体CD137L），并使用分子动力学模拟探索了它们与CD137的相互作用。我们的研究结果表明，与二聚体形式相比，三聚体CD137L表现出更高的热稳定性，但与CD137的结合亲和力降低，CD137L的A'B'环在结构稳定性和促进CD137相互作用中都起着关键作用。值得注意的是，六聚体结构的形成增强了结合亲和力和稳定性。这项研究为CD137L/CD137双向信号传导机制提供了有价值的见解，这可能为下一代CD137激动剂的设计提供参考。最终，这些进展可能会改善癌症免疫治疗策略，旨在通过更有效和有针对性的治疗提高患者的治疗效果。
