Succinylation - encoded metabolic codes: cracking the molecular logic of cellular adaptation

Succinylation, a recently recognized post-translational modification of lysine, has been found to be of crucial importance in the metabolic reprogramming of tumors. Succinylation plays a significant role in determining the metabolic state of cells by regulating the activities and stability of key enzymes in metabolic pathways such as the tricarboxylic acid (TCA) cycle, oxidative phosphorylation, fatty acid metabolism, and glycolysis. In addition to that, succinylation regulates immune checkpoint molecules (e.g., PD-L1, CD47), antigen presentation, and tumor immune microenvironment homeostasis. Recent studies illustrate that desuccinylase (e.g., SIRT5 and SIRT7) and succinyltransferase (e.g., KAT2A, CPT1A, HAT1, and alpha-KGDH) expression and malfunction are strongly related to immune escape of cancer. Accordingly, it has the potential for adjuvant drug targets after surgical treatment. Integrating small-molecule agents that modulate succinylation-related enzymes with surgical intervention represents a novel therapeutic approach aimed at decreasing tumor recurrence following surgery, augmenting immunotherapeutic responsiveness, and ultimately improving patients’ long-term survival outcomes. This review comprehensively examines the regulatory roles of succinylation in the tumor microenvironment and recent advances in oncological therapeutics, providing a theoretical foundation for integrated post-surgical cancer care and targeted therapy design, and identifying potential clinical oncology targets. Graphical abstract Lysine succinylation is the covalent modification of succinyl groups (-CO-CH ₂ -CH ₂ -COOH) to lysine residues of target proteins, which causes conformational changes and regulates their functional states. In this figure, mitochondria are used as the metabolic hub to summarize the production and consumption of succinyl-CoA in the TCA cycle and mediate the succinylation of key enzymes and transcription factors such as PDH, SDH, GLUD1, HMGCS2, and FEN1. The central region showed the negative regulation of SIRT5/SIRT7 and the positive regulation of KAT2A, alpha-KGDH, CPT1A, HAT1, and other acyltransferases. The lower part of the figure highlights that succinylation promotes tumor cell hypoxic adaptation and immune escape by stabilizing HIF-1α, inducing ROS production, and SDH dysfunction. TCA, Tricarboxylic acid cycle PDH, Pyruvate dehydrogenase SDH, Succinate dehydrogenase GLUD1, Glutamate dehydrogenase 1 HMGCS2, 3-hydroxy-3-methylglutaryl-CoA synthase 2 FEN1, Flap endonuclease 1, SIRT, Sirtuin family proteins, KAT2A, Lysine acetyltransferase 2A alpha-KGDH, Alpha-ketoglutarate dehydrogenase CPT1A, Carnitine palmitoyltransferase 1A HAT1, Histone acetyltransferase 1 HIF-1α, Hypoxia-inducible factor 1 alpha ROS Reactive oxygen species. This figure was created by Biorender.com.(https://BioRender.com)