Therapeutic opportunities to modulate immune tolerance through the metabolism-chromatin axis

The ability of the immune system to discriminate external stimuli from self-components - namely immune tolerance - occurs through a coordinated cascade of events involving a dense network of immune cells. Among them, CD4⁺CD25⁺ T regulatory cells are crucial to balance immune homeostasis and function. Growing evidence supports the notion that energy metabolites can dictate T cell fate and function via epigenetic modifications, which affect gene expression without altering the DNA sequence. Moreover, changes in cellular metabolism couple with activation of immune pathways and epigenetic remodeling to finely tune the balance between T cell activation and tolerance. This Review summarizes these aspects and critically evaluates novel possibilities for developing therapeutic strategies to modulate immune tolerance through metabolism via epigenetic drugs.