Dendritic cells: understanding ontogeny, subsets, functions, and their clinical applications

Abstract

Dendritic cells (DCs) play a central role in coordinating immune responses by linking innate and adaptive immunity through their exceptional antigen-presenting capabilities. Recent studies reveal that metabolic reprogramming-especially pathways involving acetyl-coenzyme A (acetyl-CoA)-critically influences DC function in both physiological and pathological contexts. This review consolidates current knowledge on how environmental factors, tumor-derived signals, and intrinsic metabolic pathways collectively regulate DC development, subset differentiation, and functional adaptability. Acetyl-CoA emerges as a dual-function metabolite, serving not only as an energy carrier but also as an epigenetic regulator that controls DC fate via lipid biosynthesis, mitochondrial metabolism, and chromatin modification. In the tumor microenvironment (TME), DCs may experience immune suppression polarization and insufficient T cell activation due to disrupted acetyl-CoA related metabolic pathways. While existing DC-based therapies remain constrained by TME-induced metabolic limitations, emerging approaches that restore acetyl-CoA related metabolic pathways balance show enhanced antitumor efficacy. The review further examines distinct metabolic adaptations among DC subsets and their relevance to autoimmune diseases, infectious immunity, and transplant outcomes. By integrating current research on targeting DC metabolic targets, we outline strategies for developing immunotherapies that target DC metabolic flexibility. Remaining hurdles include tailoring interventions to specific subsets, refining metabolic manipulation techniques, and addressing TME heterogeneity through combination therapies. These findings position acetyl-CoA as a key therapeutic target for recalibrating immunometabolism circuits, with significant implications for DC-focused cancer treatment.

Keywords: Acetyl-CoA; Cancer therapy; Dendritic cells; Immunotherapy; Metabolic reprogramming; Tumor microenvironment.

Fig. 1

Differentiation and development of DCs. MMP differentiates into CMP and CLP in the bone marrow. CMP differentiates into GMP and MDP, with GMP differentiating into monocytes and becoming moDC in inflammation. MDP differentiates into CDP, which differentiates into pre-pDC and pre-cDC. Pre-cDC is the precursor of both cDC1 and cDC2. It differentiates towards cDC1 under the control of IRF8 and towards cDC2 under the control of IRF4. The differentiation of pre-pDC into pDC depends on transcription factors like E2-2. DC subsets express markers and perform functions. CDP, common DC progenitors; CLP, common lymphoid precursor; CMP, common-myeloid progenitors; MDP, Monocyte-dendritic cell progenitors; MPP, multipotent blood progenitors

Fig. 2

Acetyl-CoA related metabolism. Glucose produces pyruvate, which is converted into acetyl-CoA and enters the TCA cycle, providing the conditions for OXPHOS to occur. In mitochondria, acetic acid and BCAA serve as additional sources of acetyl-CoA. The intermediate metabolites generated by acetyl-CoA in the TCA cycle exert a significant influence on cellular metabolism and function. α-KG can be interconverted with Glu, and citrate can be used as an acetyl-CoA carrier to enter the cytoplasm and participate in lipid metabolism. Citric acid is broken down into acetyl-CoA, which is used to produce fatty acids and cholesterol. Fatty acids can be converted to acetyl -CoA through FAO. Additionally, acetyl-CoA have various source within the nucleus. Acetyl-CoA provides acetyl groups for histone acetylation and regulates gene expression. Furthermore, the expression and activity of acetyl-CoA related enzymes are regulated by transcription factors and signaling pathways. ACTP, acetate transporter protein; α-KG, α-ketoglutaric acid; BACA, branched chain amino acid; BCAT, branched-chain amino acid aminotransferase; CPT, Carnitine acyl transferase; HMGCL, HMG-CoA lyase; HMGCS, HMG-CoA synthase; MVA, Mevalonate; OAA, oxaloacetic acid

Fig. 3

Metabolic differences between different DC states and the regulatory role of acetyl-CoA. As DCs mature, their metabolic profile shifts. Immature DCs initially rely on glycolysis, driven by hexokinase II activated via the TBK-IKKε pathway. Pyruvate, generated from glucose, is converted to acetyl-CoA by PDC and enters the TCA cycle. The electron transport chain and OXPHOS generate ATP to support early DC differentiation, particularly into cDC1. During activation, enhanced OXPHOS and ROS production are crucial for cDC1 and cDC2 differentiation, respectively. Citrate from the TCA cycle is transported to the cytoplasm and converted to acetyl-CoA by ACLY, then to fatty acids by ACC, aiding ER and Golgi expansion. Upon sufficient antigen activation and cytokine stimulation, mature DCs maintain high glycolysis levels, supporting cytokine secretion and migration to lymph nodes. This is regulated by mTOR pathway activation, driving gene expression changes via HIF-1α. HIF-1α and iNOS-derived NO inhibit OXPHOS in mature DCs, while AMPK counteracts the effects of mTOR. The effect of acetyl-CoA on overall metabolic status may regulate mTOR and AMPK. Mature DCs exhibit elevated cytokine secretion and T cell activation but reduced antigen uptake and phagocytosis. Acetyl-CoA derivatives also regulate DC surface molecule expression and cytokine secretion

Fig. 4

The effect of acetyl-CoA on DC. a Acetyl CoA and DC metabolism. Pyruvate produced by DC glycolysis is converted to acetyl-CoA to enter TCA cycle, catalyzed by PDC and transported by MPC. Acetyl-CoA regulates the expression of the HIF gene, which inhibits PDC activity via PDK, leading to impaired glycolysis. Acetyl-CoA prepares for oxidative phosphorylation through the TCA cycle, which generates ROS. The accumulation of ROS leads to lipid peroxidation and ER stress, impairing antigen processing and presentation. The lipid synthesis of DCs is also initiated by acetyl-CoA, which is catalyzed by the ACC to produce Mal-CoA. Acetyl-CoA can regulate the activity of mTOR to further influence the overall metabolic phenotype of the cell. Mal-CoA inhibits the mTOR pathway by suppressing Raptor. Mal-CoA also synthesizes lipids, which may contribute to the accumulation of oxidized lipids that interfere with the immune response. b Acetyl CoA and DC function. In the nucleus, acetyl-CoA affects histone acetylation, which controls the expression of genes involved in immune function. Outside the nucleus, glycolysis occurs with CCR7 oligomerization. Citric acid and cholesterol affect CD80/86 expression and MHC stability. The above processes may be regulated by mTOR, affecting DC functions such as antigen presentation, cytokine secretion and migration. This suggests a link between acetyl-CoA and DC function. PDK, pyruvate dehydrogenase kinase

Fig. 5

The therapeutic potential of acetyl-CoA. DC vaccines are the most widely used DC-based immunotherapy. By collecting blood from patients and sorting the cells, we can induce differentiation and maturation using activating factors. Acetyl-CoA may target the metabolism to control differentiation and maturation, and modulating this process with acetyl-CoA may further promote the generation of more effector phenotypes of DC. Co-culturing tumor antigens with activated DCs to load them with antigens and using acetyl-CoA to modulate tumor autophagy and DC phagocytosis may help tum our vaccines work better. The efficacy of antigen-loaded DCs re-infused into the patient depends on T cells being activated by molecules like IL-12 and CD80/86. The effect of acetyl-CoA on these molecules shows promise in improving DC efficacy. Acetyl-CoA affects other cells in the TME, making it a fully integrated strategy for therapeutic development