Macrophages in T cell-mediated rejection of renal allografts: pathological mechanisms and CAR-macrophage immunotherapy

Acute T cell-mediated rejection (TCMR) remains an important cause of early and intermediate-term graft dysfunction after kidney transplantation. As effector cells that bridge innate and adaptive immunity, macrophages are deeply implicated in the initiation, progression, and fibrotic sequelae of TCMR. This review synthesizes their multifaceted pathological roles: antigen presentation and T cell activation during early rejection, pro-inflammatory polarization driving parenchymal injury, chemokine-mediated recruitment that sustains immune infiltration, and macrophage-to-myofibroblast transition (MMT) underlying interstitial fibrosis in chronic graft deterioration. Because conventional immunosuppression is systemic and incompletely addresses the intragraft immune microenvironment, we further examine chimeric antigen receptor macrophages (CAR-Ms) as an emerging strategy for TCMR intervention. Building on current mechanistic insight, we propose two engineering approaches: targeted-elimination CAR-Ms designed to recognize and clear pathogenic effector immune cells, and tolerance-inducing resident CAR-Ms engineered to suppress inflammation and fibrosis while promoting tolerance. Together, these macrophage-engineering strategies provide a conceptual approach to reshaping the renal allograft immune microenvironment and improving long-term graft survival.