Metabolic Checkpoint: The Core Regulator of Immune Cell Functional Plasticity and A New Target for Disease Intervention

The activation, differentiation, effector functions, and memory formation of immune cells are not only regulated by signaling pathways and transcription factors but also profoundly depend on the dynamic reprogramming of their intrinsic metabolic states. Over the past decade, groundbreaking research in the field of immunometabolism has revealed that different metabolic pathways (such as glycolysis, oxidative phosphorylation, fatty acid oxidation, and amino acid metabolism) do not merely passively provide energy and biosynthetic precursors but actively act as 'checkpoints' determining the fate of immune cells. This article systematically elaborates on the unique metabolic characteristics of major immune cell populations (including T cells, B cells, macrophages, and dendritic cells) during resting, activation, differentiation, and exhaustion. We focus on how key metabolic sensors (such as mTOR, AMPK, HIF-1α) and metabolic enzymes (such as hexokinase, LDH, IDO) integrate microenvironmental signals (such as nutrients, oxygen, cytokines) to remodel metabolic networks, thereby precisely regulating the intensity, nature, and duration of immune responses. Furthermore, we explore how immune cell metabolic disorders lead to dysfunction under pathological conditions such as tumors, autoimmune diseases, chronic infections, and aging. Finally, we envision the great potential of targeting immunometabolism as a novel therapeutic strategy, including small molecule inhibitors, nutrient interventions, and metabolically engineered cell therapies, while pointing out current research gaps and future directions. Understanding the precise regulation of immunometabolism will provide fundamental insights for the development of next-generation immunotherapies.