Overcoming the Limitations of Transplant Rejection through Macrophage Energy Metabolism Reprogramming Control
Background
Organ transplantation is the only life-saving treatment for patients with end-stage organ failure. However, it is not easy for the transplanted organ to maintain normal function for a long time in the recipient's body. Early ischemia-reperfusion injury (IRI), acute rejection, and fibrosis of the organ are major obstacles to the long-term survival of the graft. Immunosuppressive agents currently used in clinical practice primarily focus on suppressing T cell-mediated adaptive immune responses, which limits their effectiveness by not considering the unique metabolic characteristics of macrophages, a key immune cell that mediates both innate and adaptive immunity.
Macrophages exhibit remarkable plasticity, adapting their functional phenotype in response to environmental changes. A classic example is the polarization into M1 macrophages, which promote inflammation, and M2 macrophages, which mediate anti-inflammatory responses and tissue repair. Recent advances in immunometabolism have revealed that these functional changes in macrophages are regulated by metabolic reprogramming within the cell. Therefore, controlling macrophage metabolic pathways has emerged as a promising strategy to improve graft survival after transplantation.
Key Findings
The research team elucidated the molecular mechanisms underlying the dynamic metabolic pathways of macrophages during the organ transplantation process. Inflammatory M1 macrophages primarily rely on aerobic glycolysis, a process that rapidly breaks down glucose into lactate, generating energy quickly and promoting the secretion of inflammatory mediators such as IL-1β, IL-6, and TNF-α. Pyruvate Kinase M2 (PKM2), a key enzyme in glycolysis, induces M1 polarization by activating Hypoxia-Inducible Factor 1-alpha (HIF-1α), which directly drives the transcription of inflammatory genes.
In contrast, anti-inflammatory M2 macrophages primarily depend on oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) as their main energy sources. Carnitine Palmitoyltransferase 1A (CPT1A), the rate-limiting enzyme in FAO, activates FAO-driven OXPHOS in mitochondria, supporting the sustained anti-inflammatory and tissue repair functions of M2 macrophages.
These metabolic changes in macrophages are closely responsive to microenvironmental factors within the transplanted organ. In IRI conditions, where oxygen supply is temporarily blocked, hypoxia and succinate accumulation activate HIF-1α, which in turn stimulates abnormal M1 macrophage activity. Accumulated lactate within the tissue also influences macrophage metabolic signaling pathways, determining the progression of fibrosis or rejection in the graft. Carbohydrate metabolism, including glycolysis, the tricarboxylic acid cycle (TCA cycle), and the pentose phosphate pathway (PPP), along with amino acid catabolic pathways, are intricately interconnected to regulate the final phenotype of macrophages.
Significance and Prospects
This mechanistic clarification offers the potential to shift the paradigm of current immunomodulation in organ transplantation, which has been largely dependent on T cell suppression. It demonstrates that macrophage metabolic control can serve as a key therapeutic target throughout the entire process—from acute inflammatory injury in the early post-transplant phase to chronic fibrosis and graft rejection. Furthermore, the study sheds new light on the association between long-term immunosuppressive therapy and the risk of tumor recurrence, from the perspective of macrophage metabolic reprogramming. Precise control of macrophage metabolism could help maintain a balance between immune suppression and tumor surveillance.
However, for clinical application, a precise drug delivery system that specifically targets macrophage metabolic pathways is required. Systemic metabolic inhibition or activation could cause severe side effects in the energy metabolism of other normal cells. Future research is expected to focus on developing technologies that selectively correct macrophage metabolism in the transplanted organ, using nanocarriers targeting macrophage-specific receptors.
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 oncology.
These research findings can be specifically applied to the development of organ preservation solutions and post-surgical management scenarios. Adding PKM2 inhibitors to the preservation solution during the organ preservation phase before transplantation can preemptively block the initial inflammatory polarization of macrophages caused by IRI. This could serve as a practical preventive measure to reduce the incidence of hyperacute rejection immediately after transplantation. Additionally, monitoring the metabolite profile of macrophages through blood tests or tissue biopsies of transplant recipients could serve as an early diagnostic indicator of rejection. Industrially, this could lead to the development of patch-type therapeutics that locally deliver CPT1A-activating agents to the transplanted organ, or lipid nanoparticle (LNP)-based gene therapies targeting macrophages. When combined with existing chemical immunosuppressive therapies, which broadly suppress the immune system, this approach could significantly reduce drug dosage while maximizing the long-term survival of the transplanted organ.