Protein Posttranslational Modifications in Immunity: Molecular Mechanisms and Therapeutic Targets

The immune response is a highly dynamic and precisely controlled process, and relies on an intricate network of protein interactions to maintain its homeostasis. Protein posttranslational modifications (PTMs), by covalent addition of chemical groups or peptide chains, or by proteolytic cleavage, directly alter the structure, activity, electrical charge, thermal stability, and function of immune-related proteins. Here, we enumerate the main PTMs in the immune system and highlight their global regulatory roles across innate immunity, T-cell-mediated cellular immunity, and B-cell-mediated humoral immunity, including phosphorylation, ubiquitination, SUMOylation, acetylation, methylation, glycosylation, and other new types. We focus on how these modifications regulate antigen presentation and recognition, immune signal transduction, antibody production and class switching, immune contraction, immune memory establishment, as well as immune tolerance and homeostasis. Critically, dysregulation of host protein PTMs disrupts immune homeostasis, which in turn induces numerous immune-related diseases, including cancer, autoimmune diseases, and infectious diseases. By integrating mechanistic insights with emerging therapeutic strategies, this review provides a comprehensive PTM network that elucidates the molecular basis of immune-related diseases and highlights promising immunotherapeutic strategies targeting these modifications.