Macrophage polarization in organ transplantation rejection and targeted therapeutic strategies

Organ transplantation improves survival and quality of life in end-stage organ failure, but rejection remains a key barrier to long-term graft success. While current immunosuppression primarily targets adaptive immunity, its limitations and side effects necessitate alternative therapeutic strategies. Macrophages infiltrate grafts extensively, which are involved in antigen presentation function, ischemia-reperfusion injury, and both acute and chronic rejection processes. Notably, their polarization toward an anti-inflammatory phenotype may alleviate rejection and potentially contribute to graft immune tolerance. In this review, we will give an overview on macrophage phenotypes and their functional diversity in allograft rejection. Also, we will discuss emerging strategies to modulate macrophage polarization, including therapies exploiting their dual regulatory capacity, nanoparticle-based targeting systems, gene therapies, and microRNA-mediated regulation. A deeper understanding of macrophage biology in transplantation could enable more sophisticated anti-rejection approaches, whose integration with conventional immunosuppression may ultimately enhance long-term graft outcomes.