Inhibitory effect of Relatlimab on LAG3–FGL1 interaction investigated by molecular dynamics simulation

As immunotherapy becomes increasingly integrated into cancer treatment, LAG3 (lymphocyte activation gene 3) has been recognized as an immune checkpoint that plays an important role in tumor immune evasion. FGL1 (fibrinogen-like protein 1) has been identified as a ligand of LAG3 that mediates immunosuppressive effects through their interaction. While experimental evidence suggests that Relatlimab can block this interaction, the underlying molecular mechanism remains poorly understood. To investigate this, we performed molecular dynamics simulations to analyze the LAG3/FGL1 complex and its interaction with Relatlimab. Our results demonstrate that Relatlimab binding destabilizes the LAG3/FGL1 complex by inducing conformational changes, thereby weakening the overall interaction. Further analysis of key residues reveals that Relatlimab disrupts the LAG3/FGL1 binding, particularly affecting the ARG residues of LAG3 and the GLU and ASP residues of FGL1. These findings provide new insights into the mechanism by which Relatlimab inhibits immune evasion, offering potential for modulating the structure and stability of the LAG3/FGL1 complex. Additionally, we investigated the effect of Favezelimab on the LAG3/FGL1 interaction and observed an effect similar to that of Relatlimab. This study advances our understanding of the roles of Relatlimab and Favezelimab in regulating immune responses and provides valuable theoretical support for the development of cancer therapies targeting the LAG3 signaling pathway.