Research progress on protein succination modification in cancer

Metabolic dysregulation is a hallmark of cancer. Mutations in genes encoding key enzymes of the tricarboxylic acid (TCA) cycle can result in the accumulation of "oncometabolites". These metabolites play essential roles in tumor initiation, progression, and immune evasion by inhibiting enzymatic activity or driving covalent protein modifications. Accumulation of fumarate due to TCA cycle disruptions or fumarate hydratase (FH) inactivation mutation affects mitochondrial function, DNA repair, protein function, and the tumor microenvironment. As an α,β-unsaturated electrophilic metabolite, fumarate reacts with cysteine residues on susceptible proteins via Michael addition, generating stable S-(2-succinyl)cysteine (2SC) modifications, a post-translational modification process known as protein succination modification. Research has shown that protein succination modification plays a critical role in tumor initiation, progression, and immune evasion, providing new insights for cancer diagnosis and therapy. Future metabolic interventions targeting succination modification could significantly improve cancer therapies. This review offers a comprehensive overview of the role of protein succination modification in tumor metabolism and immune evasion, along with its potential clinical applications.