Yin-Yang: The Dual Role of Lactate as a Context-Dependent Immunometabolic Regulator in the Inflammatory...

Lactate, once regarded merely as the terminal product of glycolysis, is now recognised as a pivotal immunometabolic regulator that actively shapes inflammatory responses. However, accumulating evidence reveals an apparent paradox that lactate can either amplify immune activation or promote inflammation resolution depending on the biological context. The mechanisms underlying this functional duality remain incompletely understood, limiting the development of effective lactate-targeted therapies. In this review, we propose that lactate functions as a context-dependent immunometabolic rheostat whose Yin-Yang properties are determined by the integration of four key factors: lactate concentration, cellular identity, disease stage and inflammatory microenvironment. We summarise how lactate regulates immune responses through coordinated control of metabolic reprogramming, intercellular lactate shuttling, receptor-mediated signalling, intracellular sensing, and protein lactylation, thereby orchestrating the activation and resolution of inflammation. We further discuss the cell-specific actions of lactate across endothelial cells, macrophages, fibroblast-like synoviocytes, neutrophils, and lymphocytes, highlighting how these mechanisms collectively remodel the inflammatory microenvironment. Beyond mechanistic insights, we examine evidence from representative inflammatory disease models, including rheumatoid arthritis, sepsis, and atherosclerosis, and evaluate emerging therapeutic strategies targeting lactate production, transport, sensing and metabolism. Rather than advocating indiscriminate lactate inhibition, current evidence supports context-specific modulation of lactate signalling according to disease stage and immune landscape.