Macrophage metabolic reprogramming in organ transplantation: mechanisms, transplant outcomes, and therapeutic...

Organ transplantation is the definitive treatment for end-stage organ failure, yet long-term graft survival remains substantially limited by ischemia-reperfusion injury (IRI), allograft rejection, and chronic graft dysfunction. Current immunosuppressive regimens have not fully exploited the metabolic plasticity of macrophages, which are central orchestrators of both innate and adaptive immune responses in transplanted organs. Macrophages display remarkable functional plasticity, classically defined by pro-inflammatory (M1)/anti-inflammatory (M2) polarization, and this dual capacity renders them uniquely impactful in transplanted organs. Accumulating immunometabolic evidence indicates that this plasticity is governed by dynamic metabolic reprogramming orchestrated by key metabolic nodes: M1 macrophages rely primarily on aerobic glycolysis and secrete proinflammatory cytokines, such as IL-1β, IL-6, and TNF-α, whereas M2 macrophages depend on oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) to sustain anti-inflammatory and tissue-repair programs. For example, pyruvate kinase M2, a key glycolytic enzyme, promotes M1 polarization via glycolytic reprogramming and HIF-1α-dependent inflammatory gene transcription, whereas the carnitine palmitoyltransferase 1A, a rate-limiting enzyme in FAO, supports M2 polarization through FAO-driven OXPHOS. Core metabolic pathways encompass carbohydrate metabolism-glycolysis, the tricarboxylic acid cycle, and the pentose phosphate pathway-alongside FAO and amino acid catabolism. These pathways are dynamically modulated by microenvironmental cues, such as hypoxia, lactate, and succinate, and in turn dictate macrophage phenotypic identity and effector function. In this review, we comprehensively review the molecular mechanisms underpinning macrophage metabolic reprogramming, from early IRI and acute rejection to chronic rejection, fibrosis, and post-transplant tumor recurrence, linking metabolism to alloimmunity and oncological risk. Emerging therapeutic strategies target macrophage metabolism, including metabolic enzyme inhibitors such as 2-deoxyglucose, which attenuates chronic lung allograft dysfunction, cell-based therapies, nanoparticles, and gene editing, for example macrophage-specific MEK1/2 ablation via CRISPR/Cas9, which reprograms glycolysis to OXPHOS and ameliorates cardiac rejection. Harnessing these metabolic nodes may complement current immunosuppression and improve graft survival, warranting future clinical evaluation.