Unleashing the power of immune checkpoints: Post-translational modification of novel molecules and clinical applications

Immune checkpoint molecules play a pivotal role in the initiation, regulation, and termination of immune responses. Tumor cells exploit these checkpoints to dampen immune cell function, facilitating immune evasion. Clinical interventions target this mechanism by obstructing the binding of immune checkpoints to their ligands, thereby restoring the anti-tumor capabilities of immune cells. Notably, therapies centered on immune checkpoint inhibitors, particularly PD-1/PD-L1 and CTLA-4 blocking antibodies, have demonstrated significant clinical promise. However, a considerable portion of patients still encounter suboptimal efficacy and develop resistance. Recent years have witnessed an exponential surge in preclinical and clinical trials investigating novel immune checkpoint molecules such as TIM3, LAG3, TIGIT, NKG2D, and CD47, along with their respective ligands. The processes governing immune checkpoint molecules, from their synthesis to transmembrane deployment, interaction with ligands, and eventual degradation, are intricately tied to post-translational modifications. These modifications encompass glycosylation, phosphorylation, ubiquitination, neddylation, SUMOylation, palmitoylation, and ectodomain shedding. This discussion proceeds to provide a concise overview of the structural characteristics of several novel immune checkpoints and their ligands. Additionally, it outlines the regulatory mechanisms governed by post-translational modifications, offering insights into their potential clinical applications in immune checkpoint blockade.