The Role of Chimeric Antigen Receptor Regulatory T Cells in Promoting Immune Tolerance in Solid Organ Transplantation: Mechanisms and Therapeutic Potential

Solid organ transplantation (SOT) is a life-saving procedure for patients with end-stage organ failure; however, lifelong immunosuppressant use is needed to prevent allograft rejection. These drugs increase the risk of non-Hodgkin lymphoma, liver, kidney, and lung cancers, and heighten susceptibility to oncogenic viruses, including hepatitis B and Epstein-Barr virus. The usage of chimeric antigen receptor (CAR) regulatory T (Treg) cells is a promising approach to induce transplant tolerance while minimizing dependence on immunosuppressants. The CAR Tregs offer the potential to enhance graft survival and quality of life by reducing immunosuppressant-related morbidity and mortality. Despite remarkable progress in transplantation tolerance, challenges remain owing to a limited understanding of Treg biology and technical barriers. This review discusses the implications of immunosuppression, CAR and CAR Treg biology, mechanisms of Treg-mediated tolerance, CAR Treg manufacturing, clinical trials, optimization strategies, and existing challenges and future directions for CAR Treg-based therapies in SOT.