Bottleneck of metabolic reprogramming and immune surveillance barrier: the implicit blind spot of lysine succinylation. Tumor cells undergo metabolic reprogramming, aberrantly redirecting intracellular metabolic pathways to survive within the harsh tumor microenvironment (TME) and evade T‑cell immune surveillance. Recently, lysine succinylation—a dynamic post‑translational modification (PTM) that attaches a succinyl group to lysine residues—has emerged as a key link between metabolic rewiring and immune deficiency. However, the precise enzyme‑substrate relationships governing when, where, and by which enzymatic induction succinylation markers generate real‑time asymmetry in cancer cells have remained obscure. This lack of molecular‑biophysical resolution constitutes a critical technical bottleneck that prevents screening for the acquired resistance to immune checkpoint inhibitors (ICIs) that frequently arises during therapy.

Writer–Eraser network of succinylation enzymes and control of PD‑L1 checkpoint stability. To delineate the epigenetic‑metabolic molecular control system, we hierarchically mapped the intracellular enzyme architecture that drives succinylation dynamics. The team demonstrated a counterbalancing kinetic relationship between writer enzymes—including CPT1A and KAT2A—and eraser enzymes such as SIRT5 and SIRT7 that remove the modification. Notably, this enzyme network directly promotes succinylation of the immune‑evasion master protein PD‑L1 (Programmed death‑ligand 1), thereby inducing proteasomal degradation kinetics. This mechanism is organically synchronized with metabolites of the tricarboxylic acid (TCA) cycle and glycolysis, functioning as a backbone that simultaneously regulates tumor growth signaling and immunosuppressive phenotype.

Metabolic‑intervention–based restoration of immune phenotype and establishment of immunogenic cell death (ICD) kinetics. The therapeutic breakthrough of this study lies in the combined activation of small‑molecule inhibitors and localized metabolic‑intervention protocols to normalize the abnormal polarization of tumor‑infiltrating immune cells. Blocking the CPT1A·KAT2A writer enzymes or precisely tuning the activity of SIRT5·SIRT7 resulted in linear restoration of cytotoxic activity of macrophages, dendritic cells, and target T cells that had been incapacitated within the TME. Moreover, tumor cell death released tumor‑specific antigens, dramatically accelerating the conversion rate to ICD and thereby completely dismantling the resistance barrier of conventional checkpoint inhibitors, as demonstrated by synergistic therapeutic valleys.

Establishment of a precision metabolic‑immune combinatorial therapy platform and standardization of multi‑omics in silico simulations. This PTM protein‑engineering and metabolism‑immunology integrated data white paper delivers a disruptive impact on next‑generation anticancer drug R&D and personalized oncology platforms. Prognostic guidelines for cancer patients are reset from static DNA‑sequence analysis to a ‘metabolome‑PTM coupled spatiotemporal heterogeneity reverse‑engineering protocol.’ The generated succinylation map integrates CRISPR screening and AI‑based structural prediction models, becoming the computational standard for filtering immune‑resistance drivers from single‑cell multi‑omics datasets. Consequently, it serves as a master reference to eliminate metabolic false‑positive noise in clinical trial cohorts and to dramatically shorten global IND approval timelines for combinatorial immunotherapies.