State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China.
Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Science, Sun Yat-Sen University, Guangzhou 510006, China.
J Med Chem. 2024 Aug 22;67(16):13778-13787. doi: 10.1021/acs.jmedchem.4c00583. Epub 2024 Aug 12.
Metal-based chemoimmunotherapy has recently garnered significant attention for its capacity to stimulate tumor-specific immunity beyond direct cytotoxic effects. Such effects are usually caused by ICD via the activation of DAMP signals. However, metal complexes that can elicit antitumor immune responses other than ICD have not yet been described. Herein, we report that a rhodium complex () triggers potent antitumor immune responses by downregulating Wnt/β-catenin signaling with subsequent activation of T lymphocyte infiltration to the tumor site. The results of mechanistic experiments suggest that ROS accumulation following treatment is a critical trigger of a decrease in β-catenin and enhanced secretion of CCL4, a key mediator of T cell infiltration. Through these properties, exerts a synergistic effect in combination with PD-1 inhibitors against tumor growth . Taken together, our work describes a promising metal-based antitumor agent with a noncanonical mode of action to sensitize tumor tissues to ICB therapy.
金属基化学生物疗法最近因其能够刺激肿瘤特异性免疫的能力而受到极大关注，这种作用通常是通过 ICD 激活 DAMPs 信号来实现的。然而，能够引发除 ICD 以外的抗肿瘤免疫反应的金属配合物尚未被描述。在此，我们报告一种铑配合物 () 通过下调 Wnt/β-catenin 信号，随后激活 T 淋巴细胞浸润肿瘤部位，引发强烈的抗肿瘤免疫反应。机制实验结果表明， 处理后 ROS 的积累是 β-catenin 减少和 CCL4 分泌增强的关键触发因素，CCL4 是 T 细胞浸润的关键介质。通过这些特性， 与 PD-1 抑制剂联合对肿瘤生长产生协同作用。总之，我们的工作描述了一种有前景的金属抗肿瘤剂，它具有非典型的作用模式，使肿瘤组织对 ICB 治疗敏感。
