Tolerogenic Dendritic Cell Identity for the Treatment of Immune‐Mediated Diseases: A Signalling–Metabolism–Epigenetic Axis

Tolerogenic dendritic cells (tolDCs) maintain immune tolerance by suppressing effector T cells while inducing regulatory T cells (Treg). Importantly, tolDCs play critical roles in suppressing pathogenic activation and maintaining homeostasis in immune-mediated diseases. This highlights the need to define the molecular mechanisms sustaining their stable tolerogenic identity. Although tolDCs are typically characterized by downregulated co-stimulatory molecules and upregulated anti-inflammatory cytokines, this phenotype alone fails to fully define their tolerogenic nature. Emerging evidence links signalling pathways, metabolic adaptation and epigenetic regulation in shaping the tolDC landscape. While acting through different initial receptors, distinct tolerogenic stimuli─such as 1,25-dihydroxyvitamin D3 (VitD3), dexamethasone (Dex) and rapamycin─converge on core signalling regulators, including mammalian target of rapamycin (mTOR), AMP-activated protein kinase (AMPK) and signal transducer and activator of transcription 3 (STAT3). These central checkpoints directly drive metabolic reprogramming, encompassing oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), tricarboxylic acid (TCA) cycle and glycolysis. These metabolic adaptations subsequently reshape chromatin organization through metabolite-dependent regulation of DNA methylation and histone modification. Accordingly, metabolite-mediated epigenetic remodelling effectively locks these pathways to stabilize the tolerogenic state, fixing the enzymatic and secretome programmes required for robust Treg polarization despite phenotypic plasticity. This review discusses the signalling pathways driving tolerogenic metabolic adaptation, the mechanisms linking metabolism to epigenetic regulation and the implications of this signalling-metabolism-epigenetic axis for tolDC identity, immune regulation and therapeutic applications in immune-mediated and inflammatory diseases, as well as in transplantation.