Succinylation in Cancer Immunotherapy: A Review of PD-L1 Reduction and Immune Evasion
A protein modification linking metabolic state and immune function
Protein succinylation can both help cancer cells evade immunity and strengthen antitumor immunity. This review in Frontiers in Immunology synthesizes prior literature on these opposing effects and outlines remaining challenges for therapeutic targeting and biomarker development. It does not report new experiments or treatment effects in patients.
Succinylation is a post-translational modification in which a succinyl group is added to lysine residues in proteins. It affects lysine charge and protein structure, altering enzyme activity or protein stability. Succinyl coenzyme A (succinyl-CoA), the source of the succinyl group, is linked to the citric acid cycle, connecting cellular metabolic state with changes in protein function.
The modification occurs not only on histones but also on various metabolic proteins. Succinylation as a whole therefore cannot be explained solely as epigenetic regulation. Both enzyme-mediated reactions and nonenzymatic formation have been reported, and the effects vary with the target protein and cellular context.
PD-L1 reduction and immunosuppressive metabolism coexist
The review discusses proteins reported to promote succinylation, including carnitine palmitoyltransferase 1A (CPT1A) and lysine acetyltransferase 2A (KAT2A), as well as sirtuin family members such as SIRT5 and SIRT7, which remove the modification. Evidence is insufficient, however, to classify all proteins that promote succinylation as dedicated succinyltransferases. CPT1A’s primary physiological role is associated with mitochondrial fatty acid oxidation; its succinylation-promoting activity has been reported under specific experimental conditions.
A prominent example of immune checkpoint regulation is programmed death-ligand 1 (PD-L1). In models including melanoma cited by the review, CPT1A is described as promoting succinylation of PD-L1 at lysine 129 and contributing to PD-L1 degradation and reduced cell-surface expression. This acts in a direction that alleviates suppression of CD8-positive T cells. Conversely, in that context, CPT1A inhibition is linked to PD-L1 accumulation, making it difficult to conclude that blocking the enzyme will always have an antitumor effect. The review’s accounts of the degradation pathway are inconsistent, so the pathway cannot be established from this material alone.
There are also examples pointing in the opposite direction. Succinylation of lactate dehydrogenase A (LDHA), phosphoglycerate kinase 1 (PGK1), and other proteins can promote glycolysis and lactate accumulation in cancer cells, potentially contributing to an immunosuppressive environment. Distinct metabolic and functional changes have also been reported in macrophages, dendritic cells, and T cells. In head and neck squamous cell carcinoma, the review describes an example linking gasdermin E (GSDME) succinylation to pyroptosis, an inflammatory form of cell death, but the evidence does not support extending this finding to a general ability to overcome immunotherapy resistance.
Validation still needed for therapeutic targets and biomarkers
The review surveys small molecules targeting succinylation-regulating enzymes, metabolic interventions, and combination strategies with existing therapies. However, results from different cancer types and experimental systems cannot be combined as though they were outcomes from a single therapy. The possibility that interventions suppressing cancer-cell growth may also affect normal immune cells must be assessed.
Associations between succinylation patterns and prognosis remain exploratory. Standardized detection platforms and large-scale clinical validation are lacking, and direct clinical validation as a predictor of response to immune checkpoint inhibitors remains to be done. Mechanistic studies also rely substantially on correlation analyses and cell-line models.
The next tasks include defining enzyme–substrate relationships and mapping changes over time and across locations within tumors. Integrating gene-function screening, artificial intelligence predictions, and single-cell multiomics is proposed as a research direction. These approaches do not constitute established patient-selection tools or computational standards.
Source: Original review in Frontiers in Immunology.
Oncology & Metabolic Immunotherapy Core, Published May 2026. DOI: [Source Generated Data]
Summary: Elucidating the programmatic intersections link metabolic reprogramming with tumor immune evasion, this study maps the dynamic configurations of lysine succinylation across the tumor microenvironment (TME). Governed by an enzymatic network of writers (CPT1A, KAT2A) and erasers (SIRT5, SIRT7), this post-translational modification (PTM) interlocks directly with the TCA cycle and glycolytic kinetics to dictate oncogenic signaling. Crucially, the framework establishes that site-specific succinylation programmatically alters immune checkpoint architecture, driving the targeted degradation of PD-L1 to diminish localized immunosuppression. By combining small-molecule enzymatic inhibitors with precise metabolic tuning, the platform successfully restores phenotypic cytotoxicity across compromised macrophage, dendritic cell, and T-cell lineages while amplifying immunogenic cell death (ICD) cascades, providing a scalable computational baseline for universal precision immunotherapies.
Before targeting succinylation therapeutically, researchers need to distinguish which proteins change in which cells, rather than focusing on overall modification levels. For example, broadly inhibiting CPT1A in an experiment aimed at reducing PD-L1 could produce a change in the opposite direction from the one intended. Follow-up studies could distinguish cancer cells from immune cells and measure target-site succinylation, PD-L1 expression, and T-cell function together. Biomarker development requires linking quantitative proteomics data with patient treatment-response data to validate predictive performance. This review helps frame questions for future experiments; it does not provide a basis for changing patient prescriptions or diets.