Therapeutic classes, development stage, and translational limitations in tolerance reprogramming.
| Modality | Target pathway (metabolic/epigenetic/cellular) | Mechanism of tolerance reprogramming | Disease evidence | Stage (preclinical/phase I/phase II/clinical use) | Limitations/challenges | References |
|---|---|---|---|---|---|---|
| AMPK activators (e.g., metformin, AICAR) | Metabolic | Restore OXPHOS, reduce glycolysis, lower ROS; support Treg survival and mitochondrial fitness | RA, SLE, vasculitis (immunometabolic and clinical data) | Clinical use (repurposed); formal tolerance-focused trials mostly phase II /exploratory | Indirect effects; variable efficacy across patients; limited specificity for immune subsets | [242, 243] |
| NAD+ boosters (NR, NMN, nicotinamide) | Metabolic | Increase NAD+ → enhance sirtuin activity; promote histone deacetylation; improve mitochondrial quality and regulatory-cell stability | Preclinical models of arthritis, lupus, and inflammatory aging | Preclinical; early human studies in metabolic/aging contexts | Limited clinical efficacy in RA; inconsistent effects on Treg function; unclear target engagement | [244–246] |
| PPAR-γ agonists (e.g., pioglitazone) | Metabolic | Reprogram lipid metabolism; suppress NF-κB; favor oxidative and anti-inflammatory phenotypes in immune and stromal cells | Experimental arthritis and fibrosis models; limited rheumatic clinical data | Clinical use in diabetes; preclinical/early translational in rheumatology | Systemic metabolic effects, weight gain, and limited immune-specific targeting | [247] |
| HDAC inhibitors | Epigenetic | Increase histone acetylation at regulatory loci; enhance Treg function; compress inflammatory chromatin accessibility | Arthritis and lupus models; small early-phase human data | Preclinical and phase I/II | Off-target epigenetic effects; toxicity with chronic use; limited selectivity | [248, 249] |
| BET inhibitors | Epigenetic | Disrupt BRD4/super-enhancer complexes at TNF, IL6, CXCL loci; reduce sustained inflammatory transcription | Preclinical RA and tissue-inflammation models | Preclinical; some early oncology trials, limited immune-tolerance trials | Hematopoietic toxicity (e.g., thrombocytopenia); off-target transcriptional effects; narrow therapeutic window | [146, 158, 250] |
| EZH2 inhibitors | Epigenetic | Reduce H3K27me3 at silenced regulatory genes (e.g., SOCS3, CDKN1A); relieve repression of tolerogenic programs | B cells and FLS in RA and SLE; strong preclinical rationale | Preclinical and early clinical (mainly oncology); rheumatic use exploratory | Risk of global chromatin dysregulation; unclear long-term safety in non-malignant disease | [94, 147] |
| Low-dose DNMT inhibitors | Epigenetic | Partially reverse pathological DNA hypermethylation at tolerance genes; re-open FOXP3 and IL10 loci | Preclinical models of autoimmunity; conceptual alignment with epigenetic drift data | Preclinical; early clinical experience in oncology | Risk of global hypomethylation; potential oncogenic effects; dose optimization challenges | [251, 252] |
| CAR-Tregs | Cellular | Antigen-specific suppression at inflamed sites; stable FOXP3 expression and local IL-10/TGF-β delivery | Strong preclinical efficacy in arthritis, colitis, and transplantation models | Preclinical; early phase I trials in other immune contexts | Limited in vivo persistence; phenotypic instability; high cost and manufacturing complexity | [253, 254] |
| Tolerogenic dendritic cells (tolDCs) | Cellular | Present self-antigen with low costimulation; induce and expand Tregs; dampen effector priming | Phase I/II trials in RA and other autoimmune diseases are showing safety and biological activity | Phase I/phase II | Variable durability; scalability challenges; patient-to-patient variability | [255, 256] |
| MSC-based and EV-based therapies | Cellular/paracrine | Deliver tolerogenic cytokines, metabolites, and miRNAs; remodel immune and stromal metabolic-epigenetic states | Early trials in RA, SLE, and systemic sclerosis (SSc); preclinical evidence of regulatory reprogramming | Phase I/phase II; some compassionate/controlled clinical use | Heterogeneity of preparations; unclear mechanism consistency; regulatory complexity | [257, 258] |
| Nanoparticle-targeted metabolic/epigenetic agents | Delivery/metabolic/epigenetic | Cell- or tissue-specific delivery of metabolic/epigenetic drugs to synovium or lymphoid organs; limit systemic toxicity | Robust preclinical data in arthritis and systemic inflammation | Preclinical | Limited tissue penetration; delivery efficiency challenges; manufacturing scalability | [259, 260] |
| Integrated multi-omic/digital-twin–guided regimens | Systems/computational | Use epigenomic, transcriptomic, and metabolomic signatures to tailor and adapt tolerance-reprogramming therapies over time | Emerging computational and pilot translational studies | Conceptual and early translational; not yet in routine clinical practice | Lack of validated clinical biomarkers; high cost; limited clinical integration | [261–263] |
AICAR: 5-aminoimidazole-4-carboxamide ribonucleotide; AMPK: AMP-activated protein kinase; BET: bromodomain and extra-terminal; BRD4: bromodomain-containing protein 4; CAR-Tregs: chimeric antigen receptor regulatory T cells; CDKN1A: cyclin dependent kinase inhibitor 1A; CXCL: C-X-C motif chemokine ligand; DNMT: DNA methyltransferase; EV: extracellular vesicle; FLS: fibroblast-like synoviocytes; FOXP3: forkhead box P3; HDAC: histone deacetylase; IL: interleukin; MSC: mesenchymal stem cell; NMN: nicotinamide mononucleotide; NR: nicotinamide riboside; OXPHOS: oxidative phosphorylation; PPAR-γ: peroxisome proliferator-activated receptor gamma; RA: rheumatoid arthritis; ROS: reactive oxygen species; SOCS3: suppressor of cytokine signaling 3; SLE: systemic lupus erythematosus; TGF-β: transforming growth factor beta; TNF: tumor necrosis factor.
OAA: Conceptualization, Investigation, Visualization, Writing—original draft. MMN: Conceptualization, Investigation, Methodology, Project administration, Supervision, Validation, Visualization, Writing—original draft, Writing—review & editing. Both authors read and approved the submitted version.
The authors declare no conflict of interest.
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