Succinylation in cancer immunotherapy: mechanisms, biomarkers, and therapeutic implications.

Succinylation, a dynamic post-translational modification characterized by the addition of a succinyl moiety to lysine residues, has emerged as a pivotal regulator at the interface of metabolic reprogramming and immune surveillance in cancer. This review systematically delineates the molecular mechanisms and therapeutic implications of succinylation in cancer immunotherapy. We detail the writers (e.g., CPT1A, KAT2A), erasers (e.g., SIRT5, SIRT7), and readers that constitute the enzymatic systems governing its dynamics, as well as its profound impact on core metabolic networks including the TCA cycle and glycolysis, thereby fueling tumor progression. Crucially, succinylation has been shown to regulate the tumor immune microenvironment by regulating immune checkpoint stability (e.g., promoting PD-L1 degradation), shaping the polarization and function of macrophages, dendritic cells, and T cells, and influencing immunogenic cell death. These modifications create a complex duality, capable of both enhancing anti-tumor immunity and facilitating immune evasion. We further summarize emerging therapeutic strategies, including small-molecule inhibitors targeting succinylation enzymes, metabolic interventions, and combination therapies designed to harness this pathway to overcome immunotherapy resistance. Finally, we discuss current challenges such as the incomplete mapping of enzyme-substrate relationships and the spatiotemporal heterogeneity of modifications within tumors, while highlighting future directions integrating CRISPR screening, AI prediction models, and single-cell multi-omics to advance precision targeting of succinylation for innovative cancer immunotherapies.