Reprogramming immunometabolism: linking nutrient sensing, cell death, and therapeutic innovation

Development of Immunometabolism as a central paradigm in the modern immunology has revolutionized the understanding of metabolism from being a passive supplier of energy to an important determinant of immune cell fate and function. Immune cells are activated, differentiated, survive and undergo programmed cell death through the activity of distinct metabolic programs, including those involving glycolysis, oxidative phosphorylation (OXPHOS), nutrient sensing through Mechanistic Target of Rapamycin (mTOR), AMP-Activated Protein Kinase (AMPK), and HIF‑1α. Rapid proliferation and production of cytokines by effector T cells and pro-inflammatory macrophages is mediated by glycolysis, while persistence and tolerance by memory T cells and reparative macrophages is mediated by oxidative metabolism. Metabolic input and output are also coupled with immune specialization and cell death mechanisms, such as apoptosis, Pyroptosis and ferroptosis, via mitochondrial bioenergetics and production of Reactive Oxygen Species (ROS). Altered immunometabolism is linked to a variety of pathologies: competition for nutrients in tumor physiology leads to T cell exhaustion; an unchecked glycolytic pathway maintains a state of autoimmune inflammation; pathogens exploit host metabolism to escape immunological control; and metabolic diseases, such as obesity and diabetes, foster chronic low‑grade inflammation. Therapies such as rapamycin, metformin, glycolysis and glutamine inhibitors, and metabolic adjuvants in vaccines underscore the translational potential of targeting metabolic checkpoints. But there are still debates on the specificity of the metabolic intervention, the balance between the effector and regulation responses, and the restrictions of the existing experimental models. New strategies, such as single-cell metabolomics and precision medicine, are expected to bring in more sophisticated ways for fine-tuning immune metabolism. Immunometabolism is thus a paradigm shift, with metabolism now being at the heart of immune regulation, and providing new opportunities for critical evaluation and translational innovation in cancer, autoimmunity, infections and metabolic disease.