Warburg redefined: Metabolites, mitochondria and macrophages in immune regulation

Nearly 100 years ago, Otto Warburg observed that cancer cells preferentially use glycolysis even in the presence of oxygen, supporting rapid cell growth. Since then, the concept of the Warburg effect has expanded far beyond tumour bioenergetics and is now recognised as a key feature of immune cell activation. A notable example is in macrophages, which, following pro-inflammatory stimulation, undergo Warburg-like metabolic reprogramming, characterised by increased glycolysis. Recent studies have shown that accumulated metabolites such as lactate have a range of immunoregulatory functions that shape macrophage inflammatory responses. In addition, glycolytic enzymes have been found to exert non-canonical functions that directly regulate macrophage immune signalling. Mitochondria, once considered suppressed during Warburg reprogramming, also undergo profound changes, with the electron transport chain generating reactive oxygen species and metabolites such as succinate, fumarate and itaconate playing complex immunoregulatory roles, and mitochondrial dynamics actively shaping metabolism and immune responses. Together, these findings redefine the Warburg effect in macrophages as a coordinated metabolic and signalling process that integrates glycolysis, mitochondrial function and immunometabolite signalling to optimise context-dependent immune responses.