Macrophages, among the most ancient immune cells, perform a multitude of roles ranging from phagocytosis to antigen presentation. In the context of transplantation, they are the first responders to ischemia–reperfusion injury (IRI), wherein donor organ macrophages become activated by cellular damage and reactive oxygen species. This activation polarizes them into a proinflammatory M1 phenotype, releasing cytokines such as IL-6, TNF-α, and MCP-1, which exacerbate inflammation, recruit recipient immune cells, and contribute to vascular pathology by promoting smooth muscle cell proliferation and neointimal hyperplasia.

As the immune response progresses, these M1 macrophages transition toward an anti-inflammatory M2 phenotype, notable for their involvement in tissue repair and fibrosis. M2-like macrophages secrete fibrogenic mediators like TGF-β, triggering cardiac fibroblast transformation into myofibroblasts that drive extracellular matrix deposition and fibrosis—hallmarks of chronic rejection that culminate in graft dysfunction. Importantly, not all macrophage populations are detrimental; tissue-resident macrophages derived from the donor may exert protective functions, and regulatory macrophages producing IL-10 can enhance graft tolerance by promoting regulatory T cell differentiation.

The review underscores the limitations of the conventional binary M1/M2 classification, highlighting the heterogeneity and plasticity of macrophage subsets, including CCR2-positive and CCR2-negative populations that differentially influence graft survival. Integration of emerging single-cell and spatial transcriptomics technologies now enables high-resolution mapping of macrophage phenotypes within graft tissues, revealing complex microenvironmental interactions previously unrecognized.

Therapeutically, targeting macrophage signaling pathways offers promising avenues to mitigate chronic rejection. Inhibition of the purinergic P2X7 receptor can prevent M2 polarization and fibrosis, while modulation of the mTOR/NF-κB axis via nanoparticle-delivered inhibitors has shown potential for prolonging graft survival. Epigenetic regulators like BRD4 within the BET family are also being explored to disrupt pro-fibrotic gene expression. Furthermore, repurposing FDA-approved agents such as ROCK inhibitors (belumosudil, fingolimod) could interfere with cytoskeletal dynamics critical for macrophage-mediated tissue remodeling.

The confluence of these insights heralds a conceptual shift in transplantation immunology, encouraging the development of macrophage-centric diagnostic and therapeutic strategies. Non-invasive liquid biopsies detecting donor cell-free DNA and miRNA, complemented by sophisticated omics approaches, could revolutionize monitoring of chronic rejection and prompt timely interventions.

As our understanding of macrophage diversity and function continues to evolve, this paradigm promises to overcome longstanding hurdles in graft longevity. Integrating innate immune regulation with adaptive responses may ultimately transform clinical management, turning chronic rejection from an inevitable outcome into a manageable condition.

Subject of Research: Not applicable
Article Title: Emerging features of macrophages and their intricate roles in chronic allograft rejection
News Publication Date: 30-Jun-2026
References: DOI: 10.1007/s44466-026-00046-0
Image Credits: Professor Malgorzata Kloc, Houston Methodist Hospital, USA