Phosphorylation shapes antigen presentation and immune recognition: mechanistic insights and translational perspectives

Abstract

Phosphorylation is a reversible post-translational modification that dynamically regulates immune responses by reshaping the antigen profiles. Phosphoproteomics and immunopeptidomics studies reveal that phosphorylated peptides (phosphopeptides) are naturally processed and presented by MHC class I and II molecules and can elicit robust T-cell responses. These epitopes influence proteasome cleavage, TAP transport, and MHC loading, defining the immunopeptidome under physiological and pathological states. Structurally, phosphate groups enhance MHC binding and immunogenicity, positioning phosphorylated neoantigens as promising targets for cancer immunotherapy and vaccine development. Beyond adaptive immunity, phosphorylation regulates innate signaling through Toll-like receptors (TLRs) and antigen-presenting cell activation, linking post-translational modifications to immune plasticity. Infections by parasites and bacteria such as Mycobacterium tuberculosis exploit phosphoregulation to evade antigen presentation, revealing conserved mechanisms of immune modulation. Integrating phosphoproteomic data with immune profiling may uncover new biomarkers and therapeutic strategies. This review summarizes how phosphorylation shapes antigen presentation and immune recognition across cancer, infection, and inflammation, and outlines future directions for phosphoantigen-based immunotherapy.