Platinum‐Metformin Conjugates Acting as Promising PD‐L1 Inhibitors through the AMP‐Activated Protein Kinase Mediated Lysosomal Degradation Pathway

Abstract 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.