Metabolism-driven posttranslational modifications and immune regulation: Emerging targets for immunotherapy

Abstract

The interplay between cellular metabolism and immune regulation is central to immune function and disease progression, revealing notable therapeutic opportunities. Upon activation, immune cells undergo metabolic reprogramming to meet heightened demands for energy and biosynthesis, reshaping regulatory networks across epigenomic, transcriptomic, and proteomic layers. Metabolite-derived posttranslational modifications (PTMs) serve as pivotal mechanisms integrating metabolic intermediates with immune signaling pathways. Beyond classical acetylation, diverse nonacetyl PTMs-including lactylation, succinylation, malonylation, palmitoylation, and myristoylation-modify histone and nonhistone proteins, regulating gene expression, protein stability, subcellular localization, enzymatic activity, and protein-protein interactions. Advances in mass spectrometry and bioinformatics now enable precise characterization of these PTMs, uncovering their broad roles in immune regulation. This review summarizes current progress in immunometabolism and explores future directions such as mechanistic studies, combination strategies, and clinical applications. Metabolite-driven PTMs critically connect metabolism to immune regulation, suggesting promising therapeutic approaches for cancer, autoimmune disorders, and inflammatory diseases.

Fig. 1.. Overview of metabolism in various immune cell subtypes.

Various immune cell subtypes rely on distinct metabolic pathways. In inflammatory M1 macrophages, glycolysis, the TCA cycle, the PPP, fatty acid synthesis, and amino acid metabolism are used for proliferation and the production of inflammatory cytokines. M2 macrophages depend on the TCA cycle, FAO, and arginine flux into the arginase pathway. T_eff cells use glycolysis, fatty acid synthesis, and amino acid metabolism to support rapid proliferation and cytokine production. In T_reg cells, the TCA cycle and FAO are linked to their immunosuppressive phenotypes. Memory CD8⁺ T cells require the TCA cycle and FAO to enhance the cell lifespan.

Fig. 2.. Roles of lactylation in immune cells.

Lactylation facilitates the pro-inflammatory–reparative transition of macrophages through both histone and nonhistone modifications. A high level of lactylation in TAMs promotes alternatively activated profiles. In CTLs, lactylation enhances sensitivity to activation-induced cell death. Lactylation induces a phenotypic switch of T_H17 cells to T_reg cells. It also contributes to the activation, migration, and proliferation of microglia, forming a positive feedback loop that exacerbates microglial dysfunction under pathogenic conditions. The cross-talk between lactylation and m⁶A promotes the immunosuppressive functions of TIMs.

Fig. 3.. Roles of malonylation, succinylation, and succination in immune cells.

In macrophages, malonylation and succinylation promote the production of proinflammatory cytokines, while succination exerts inhibitory effects. Succinylation can also support M2 polarization and reduce inflammation. In addition, succination inhibits pyroptosis, contributing to its anti-inflammatory effects. Succinylation plays a role in T_rm cell maldifferentiation and T_H1/T_H17 polarization, whereas succination impairs T_H1/T_H17 differentiation and cytokine production.

Fig. 4.. Roles of palmitoylation and myristoylation in immune cells.

In macrophages (upper panel), palmitoylation is involved in various innate immune signaling pathways, including the modulation of inflammasome formation, cytokine production, DNA-driven immune responses, and the pyroptotic process. Myristoylation promotes IFN expression in response to LPS stimulation and may inhibit innate antiviral immune responses. In T cells (lower panel), palmitoylation regulates TCR signaling and antitumor responses, while myristoylation facilitates T_H1 and T_H17 cell differentiation. IgG, immunoglobulin G.