Protein post-translational modifications in CAR-T cells: Novel strategies to amplify antitumor efficacy via epigenetic and metabolic circuitry.

Chimeric Antigen Receptor T cell (CAR-T) therapy has revolutionized cancer treatment, achieving remarkable success in hematological malignancies. However, its efficacy against solid tumors remains limited, primarily due to challenges such as the immunosuppressive tumor microenvironment (TME) and T cell exhaustion. Protein post-translational modifications (PTMs), including phosphorylation, ubiquitination, glycosylation, acetylation, and lactylation, are pivotal in regulating T cell signaling, activation, persistence, and metabolic adaptation, thereby offering novel opportunities to enhance CAR-T therapy. The impact of PTMs on CAR-T cell functionality is systematically explored in this review, with a particular emphasis on their regulatory roles in key processes such as T cell activation, immune checkpoint modulation, and metabolic reprogramming. Specifically, phosphorylation is crucial in governing T cell activation and exhaustion; ubiquitination is involved in modulating immune checkpoint stability; glycosylation impacts immune synapse formation; and acetylation and lactylation are key in shaping metabolic adaptations crucial for sustained CAR-T efficacy. By leveraging PTM-targeted strategies-including kinase inhibitors, deubiquitinase modulators, and metabolic pathway interventions-CAR-T therapy can be optimized to overcome its current limitations. This review highlights the transformative potential of PTM-based approaches in advancing precision cancer immunotherapy and provides a theoretical foundation for future research and therapeutic innovation.