Protein post-translational modifications and tumor immunity: A pan-cancer perspective

Protein post-translational modifications (PTMs), which involve the covalent attachment of specific chemical groups to amino acid residues, significantly reshape protein structure and function. These modifications play a crucial role in fundamental physiological processes such as signal transduction, metabolic regulation, and protein homeostasis. In the context of pan-cancer, various types of PTMs, including phosphorylation, acetylation, glycosylation, and ubiquitination, create an intricate crosstalk network that finely tunes the stability and function of immune checkpoint molecules, directly influencing tumor immune evasion and immune cell recognition. Additionally, PTMs exert multilayered regulation over the functional states of key immune cells, such as T cells, macrophages, and dendritic cells (DCs), thereby determining the intensity and nature of immune responses within the tumor microenvironment (TME). Furthermore, PTMs are pivotal in antigen processing and presentation by influencing antigen diversity and epitope display, which facilitates tumor cell escape from immune surveillance. Dynamic analyses reveal that PTM landscapes exhibit spatiotemporal specificity during tumor initiation, progression, and metastasis, closely correlating with tumor stage and the establishment of an immunosuppressive microenvironment. Based on these findings, immunotherapeutic strategies targeting key PTM-modifying enzymes, such as kinases, deacetylases, and deubiquitinases, are rapidly emerging. However, these approaches still face challenges, including drug specificity, resistance, and off-target effects. The exploration of synergistic effects through the combinational targeting of distinct PTM pathways, along with a deeper understanding of the interactive regulatory networks among PTMs, opens promising avenues for the development of next-generation precision immunotherapies. This review aims to systematically elucidate the multifaceted roles and dynamic regulation of PTMs in tumor immunity, providing a theoretical foundation and research direction for identifying novel immunotherapeutic targets and optimizing therapeutic strategies.