Post-translational modifications of immune checkpoints: molecular mechanisms, tumor microenvironment remodeling, and therapeutic implications.

Immune checkpoints play pivotal roles in regulating immune responses and maintaining tolerance. In cancer, these molecules are hijacked to suppress antitumor immunity, resulting in therapeutic resistance to immune checkpoint blockade (ICB). Recent advances have highlighted the critical role of post-translational modifications (PTMs), including phosphorylation, ubiquitination, glycosylation, palmitoylation, UFMylation, acetylation, SUMOylation, methylation, and ISGylation, in modulating checkpoint stability, trafficking, and function across diverse immune and tumor cell types. These dynamic PTMs reshape the tumor microenvironment (TME) by controlling immune cell function, antigen presentation, and inflammatory signaling. This review comprehensively outlines the mechanistic contributions of PTMs to immune checkpoint regulation, emphasizing how these PTMs orchestrate immune evasion and clinical outcomes. Special focus is given to PTMs of PD-L1, PD-1, TIM-3, TIGIT, CTLA-4, LAG-3, VISTA, BTLA, and SIRPα. We also discuss how targeting PTM-regulating enzymes or specific modification motifs offers a promising therapeutic strategy to overcome ICB resistance. Understanding the PTMs landscape provides critical insight into resistance mechanisms and unveils promising opportunities for rational combination therapies aimed at reprogramming the immunosuppressive TME and enhancing antitumor immunity.