Zhang Heng, Yang Xuemei, Xue Yue, Huang Yi, Mo Yingxi, Huang Yurun, Zhang Hong, Zhang Xiaofei, Zhao Weixin, Jia Bin, Li Ningning, Gao Ning, Yang Yue, Xiang Dongxi, Wang Shan, Qin Gao Yi, Liao Jun
School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, Peking University, Beijing, China.
Cell Discov. 2025 May 6;11(1):44. doi: 10.1038/s41421-025-00777-1.
Lactate metabolism and signaling intricately intertwine in the context of cancer and immunity. Basigin, working alongside monocarboxylate transporters MCT1 and MCT4, orchestrates the movement of lactate across cell membranes. Despite their potential in treating formidable tumors, the mechanisms by which basigin antibodies affect basigin and MCTs remain unclear. Our research demonstrated that basigin positively modulates MCT activity. We subsequently developed a basigin antibody that converts basigin into a negative modulator, thereby suppressing lactate transport and enhancing anti-tumor immunity. Additionally, the antibody alters metabolic profiles in NSCLC-PDOs and T cells. Cryo-EM structural analysis and molecular dynamics simulations reveal that the extracellular Ig2 domain and transmembrane domain of basigin regulate MCT1 activity through an allosteric mechanism. The antibody decreases MCT1 transition rate by reducing the flexibility of basigin's Ig2 domain and diminishing interactions between basigin's transmembrane domain and MCT1. These findings underscore the promise of basigin antibodies in combating tumors by modulating metabolism and immunity, and the value of a common therapeutic subunit shared by multiple transporter targets.
在癌症与免疫的背景下，乳酸代谢与信号传导错综复杂地交织在一起。基底膜蛋白（Basigin）与单羧酸转运蛋白MCT1和MCT4协同作用，协调乳酸跨细胞膜的转运。尽管基底膜蛋白抗体在治疗难治性肿瘤方面具有潜力，但其影响基底膜蛋白和单羧酸转运蛋白的机制仍不清楚。我们的研究表明，基底膜蛋白正向调节单羧酸转运蛋白的活性。随后，我们开发了一种基底膜蛋白抗体，该抗体可将基底膜蛋白转化为负向调节剂，从而抑制乳酸转运并增强抗肿瘤免疫力。此外，该抗体还改变了非小细胞肺癌患者来源的肿瘤类器官（NSCLC-PDOs）和T细胞中的代谢谱。冷冻电镜结构分析和分子动力学模拟表明，基底膜蛋白的细胞外Ig2结构域和跨膜结构域通过变构机制调节MCT1的活性。该抗体通过降低基底膜蛋白Ig2结构域的灵活性并减少基底膜蛋白跨膜结构域与MCT1之间的相互作用，降低了MCT1的转换速率。这些发现强调了基底膜蛋白抗体通过调节代谢和免疫来对抗肿瘤的前景，以及多个转运蛋白靶点共享的通用治疗亚基的价值。
