Immunoregulatory roles of post-translational modifications in colorectal cancer: mechanisms and therapeutic implications

Colorectal cancer (CRC) remains a leading cause of cancer morbidity and mortality worldwide, with tumor immune evasion posing a major challenge to effective immunotherapy. Post-translational modifications (PTMs), including phosphorylation, ubiquitination, acetylation, methylation, and glycosylation, are critical regulators of protein function and stability, profoundly influencing tumor immunogenicity and the tumor immune microenvironment. This review comprehensively examines how PTMs modulate key immune processes in CRC, such as antigen presentation, immune cell infiltration, and immune checkpoint regulation. We discuss PTM-mediated mechanisms that shape T cell exhaustion, macrophage polarization, and immunosuppressive cytokine networks within the tumor microenvironment. Moreover, we highlight the impact of PTMs on therapeutic response and resistance to immune checkpoint blockade and adoptive cell therapies. Emphasis is placed on emerging PTM-targeted strategies to enhance antitumor immunity and overcome immunotherapy resistance. Finally, we explore advances in multi-omics technologies and proteomic profiling that promise to accelerate the identification of PTM biomarkers and novel therapeutic targets. By integrating mechanistic insights with translational perspectives, this review aims to provide a foundation for leveraging PTMs to optimize immunotherapeutic approaches in colorectal cancer.