Review highlights macrophages as key drivers of chronic transplant rejection

A comprehensive review led by Professors Malgorzata Kloc and Xian Chang Li at the Immunobiology and Transplant Science Center of Houston Methodist Hospital in the United States was published in Volume 2, article number 29 of the journal Immunity & Inflammation on June 30, 2026. The article systematically examines the phylogeny, tissue origins, subsets, and functional diversity of macrophages, with a particular focus on their central role as drivers of chronic rejection. The review also summarizes emerging strategies targeting key macrophage signaling pathways, providing an important conceptual shift from a T cell-centered paradigm toward integrated innate-adaptive immune regulation in transplantation.

Organ transplantation remains the most effective treatment for end-stage organ failure, yet long-term graft survival continues to pose a major clinical challenge. While T cell-centered immunosuppressive regimens effectively control acute rejection, most grafts eventually fail due to chronic rejection. Massive infiltration of macrophages and other innate immune cells, accompanied by fibrotic changes, represents one of the most prominent pathological features of chronic rejection. Overcoming this bottleneck requires re-examining the underlying mechanisms of transplant rejection from the perspective of innate immunity.

Macrophages are the oldest cells of the immune system. Even in primitive sponges, amoeboid cells capable of rejecting foreign bodies are considered evolutionary precursors of macrophages. The core function of macrophages-phagocytosis-depends on actin and cytoskeletal dynamics, strikingly similar to that of single-celled amoebas, illustrating the evolutionary conservation of immune function. However, beyond this conservation, macrophages have evolved from simple scavengers into versatile cells with phagocytic, antigen-presenting, and immunomodulatory functions. In transplantation, this multifunctionality positions macrophages as the first cells to sense and respond to graft injury, driving vascular pathology and tissue fibrosis during chronic rejection.

Traditionally, macrophages have been simplified into pro-inflammatory M1 and pro-repair M2 polar states, but reality extends far beyond this binary classification. In addition to bone marrow-derived inflammatory macrophages, tissues harbor long-lived yolk sac-derived macrophages-such as liver Kupffer cells and cardiac resident macrophages-which play essential roles in maintaining tissue homeostasis. Following organ transplantation, donor-derived tissue-resident macrophages can be rapidly cleared by recipient NK cells and replaced by recipient-derived monocytes. Intriguingly, CCR2-positive and CCR2-negative donor-resident macrophages in cardiac allografts exert opposing effects on graft survival, suggesting that not all macrophages are detrimental. Moreover, regulatory macrophages (Mreg) have shown potential to prolong graft survival in certain clinical studies by secreting IL-10 and promoting Treg differentiation.

Chronic rejection is characterized by common pathological features including intimal hyperplasia, interstitial fibrosis, and structural destruction of the organ, with macrophages playing a critical role as key "executors" of these processes. Multiple animal models and clinical biopsies have confirmed that macrophages massively infiltrate chronically rejecting grafts, predominantly with an M2-like phenotype. In cardiac transplantation, macrophages participate in neointima formation, leading to graft vasculopathy. In renal transplantation, the extent of CD68⁺CD206⁺ M2-like macrophage infiltration correlates positively with fibrosis severity and graft loss risk. Recent studies have also identified that signaling imbalance between macrophages and Tregs is an important factor driving chronic rejection-following graft injury, Tregs secrete excessive amphiregulin, which abnormally reprograms macrophages toward a pro-fibrotic phenotype, exacerbating tissue fibrosis rather than promoting repair.

"Based on the central role of macrophages in chronic rejection, several emerging therapeutic strategies are now under investigation," the authors pointed out. The purinergic pathway, where extracellular ATP acts as a danger signal promoting M2 polarization through P2X7 receptors, can be targeted: inhibiting P2X7R effectively prevents chronic rejection in cardiac transplant models. The mTOR/NF-κB pathway selectively regulates M2 and M1 polarization, and nanoparticle-delivered mTOR/TRAF6 inhibitors have induced long-term graft survival in animal models. BET family epigenetic regulation, particularly BRD4 as a reader that selectively regulates key genes for M2 polarization, offers another target: inhibiting BRD4 blocks chronic rejection. Finally, the RhoA/ROCK pathway, which regulates actin cytoskeleton dynamics and fibrotic gene expression, is being explored as a therapeutic target: FDA-approved ROCK inhibitors such as belumosudil and fingolimod are currently being investigated for repurposing in transplantation to combat chronic rejection.

Advances in targeted therapy also demand improved diagnostic approaches. Traditional biopsy for diagnosing transplant rejection is invasive and difficult to repeat. Liquid biopsy technologies-including donor-derived cell-free DNA and miRNA-along with single-cell multi-omics are providing new tools for non-invasive diagnosis. Spatiotemporal transcriptomics offers unprecedented resolution by precisely localizing macrophage distribution and phenotypic characteristics within chronically rejecting grafts while preserving tissue architecture, opening new avenues for understanding the rejection microenvironment and identifying novel therapeutic targets.

This review systematically delineates the central role of macrophages in driving chronic rejection and provides a roadmap for shifting the field toward integrated innate-adaptive immune regulation. "As understanding of macrophage heterogeneity, plasticity, and newly discovered functions continues to advance, macrophage-targeted strategies offer promise for overcoming the limitations of current T cell-centered regimens and ultimately achieving long-term graft survival," the authors concluded.