MOE Key Laboratory of Bioinorganic and Synthetic Chemistry Guangdong Basic Research Center of Excellence for Functional Molecular Engineering GBRCE for Functional Molecular Engineering School of Chemistry, Sun Yat-Sen University, Guangzhou, 510275, People's Republic of China.
Angew Chem Int Ed Engl. 2024 Dec 2;63(49):e202410586. doi: 10.1002/anie.202410586. Epub 2024 Oct 25.
With the development of metalloimmunology, the potential of platinum drugs in cancer immunotherapy has attracted extensive attention. Although immunochemotherapy combining PD-1/PD-L1 antibodies with platinum drugs has achieved great success in the clinic, combination therapy commonly brings new problems. Herein, we have developed a platinum-metformin conjugate as a promising alternative to antibody-based PD-L1 inhibitors, not only disrupting PD-1/PD-L1 axis on cell surface but also down-regulating the total PD-L1 levels in non-small cell lung cancer (NSCLC) cells comprehensively, thus achieving highly efficient immunochemotherapy by a single small molecule. Mechanism studies demonstrate that Pt-metformin conjugate can selectively accumulate in lysosomes, promote lysosomal-dependent PD-L1 degradation via the AMPK-TFEB pathway, and modulate the upstream regulatory proteins related to PD-L1 expression (e.g. HIF-1α and NF-κB), eventually decreasing the total abundance of PD-L1 in NSCLC, overcoming tumor hypoxia, and activating anti-tumor immunity in vivo. This work suggests an AMPK-mediated lysosomal degradation pathway of PD-L1 for the first time and provides a unique design perspective for the development of novel platinum drugs for immunochemotherapy.
随着金属免疫学的发展，铂类药物在癌症免疫治疗中的潜力引起了广泛关注。虽然 PD-1/PD-L1 抗体联合铂类药物的免疫化疗在临床上取得了巨大成功，但联合治疗通常会带来新的问题。在这里，我们开发了一种铂-二甲双胍缀合物，作为抗体 PD-L1 抑制剂的有前途的替代品，不仅可以破坏细胞表面上的 PD-1/PD-L1 轴，而且可以全面下调非小细胞肺癌（NSCLC）细胞中的总 PD-L1 水平，从而通过单个小分子实现高效的免疫化疗。机制研究表明，Pt-二甲双胍缀合物可以选择性地在溶酶体中积累，通过 AMPK-TFEB 途径促进溶酶体依赖性 PD-L1 降解，并调节与 PD-L1 表达相关的上游调节蛋白（如 HIF-1α 和 NF-κB），最终降低 NSCLC 中 PD-L1 的总丰度，克服肿瘤缺氧，并在体内激活抗肿瘤免疫。这项工作首次提出了 PD-L1 的 AMPK 介导的溶酶体降解途径，并为开发用于免疫化疗的新型铂类药物提供了独特的设计视角。
