Resetting immunometabolic set points in autoimmune disease

Abstract

Autoimmune diseases often persist despite effective suppression of overt inflammation, and many patients experience relapse after treatment tapering or withdrawal. This clinical pattern raises the possibility that disease activity is influenced not only by ongoing immune stimulation, but also by relatively stable biological states that preserve inflammatory potential. In this Review, we propose immunometabolic set points as an integrative framework for examining how immune-cell metabolic programs, tissue metabolic niches, metabolite signaling, and immune or metabolic memory may interact in chronic autoimmune disease. Rather than representing a single pathway or biomarker, an immunometabolic set point is proposed to describe a potentially reversible multicompartment state shaped by immune and tissue interactions. Experimental studies support important roles for cellular metabolism, local nutrient and oxygen conditions, mitochondrial stress, stromal activation, and metabolites such as lactate, succinate, and itaconate in regulating immune function. However, their integration into a unified disease-maintaining state has not been directly established. We therefore distinguish evidence-supported mechanisms from broader conceptual inferences concerning relapse-prone remission and therapeutic reset. We further discuss how longitudinal single-cell profiling, spatial omics, metabolomics, and metabolic flux analysis may be used to test the framework and determine whether treatment produces transient inflammatory suppression or more durable biological reconfiguration.