Metabolic danger signals: TCA cycle metabolites regulate immunity and disease

Mitochondrial tricarboxylic acid (TCA) cycle metabolites have emerged as critical regulators of immunity and inflammation beyond their canonical metabolic functions. During inflammatory responses, these metabolites accumulate to millimolar concentrations in immune cells and act as endogenous damage-associated molecular patterns (DAMPs), linking metabolic state to immune regulation through receptor-dependent and receptor-independent mechanisms. Here, we characterize the inflammatory roles of TCA cycle metabolites as immunometabolites in infections, inflammatory and autoimmune diseases, and cancers. We discuss how their anti-microbial functions must be balanced against their capacity to drive and sustain inflammation. To capture the pleiotropic functions of immunometabolites, we introduce the concept of metabolic DAMPs (metaDAMPs), a class of metabolically derived danger signals that orchestrate immune responses. We highlight key metaDAMPs, including itaconate, succinate, and fumarate, and emerging immunometabolites such as malate and oxaloacetate. Finally, we highlight technological advances redefining our understanding of metabolite signaling and consider how targeting immunometabolite signaling may enable therapeutic intervention.