Engineering the Graft–Immune Interface: CAR-T Cell Strategies for Precision Organ Transplantation

Organ transplantation remains limited by a central paradox: the recipient immune system must be restrained strongly enough to preserve the graft, yet not so globally that the patient is left vulnerable to infection, malignancy, metabolic toxicity, and drug-related organ injury. This critical narrative perspective reframes rejection as an antigen-directed interaction at the graft–immune interface rather than as nonspecific inflammation. Within that framework, chimeric antigen receptor (CAR) engineering offers a plausible route to local, antigen-informed immune control. The most mature strategy is the use of donor-HLA-specific CAR regulatory T cells (CAR-Tregs), especially HLA-A2-directed products in HLA-A2-positive donor / HLA-A2-negative recipient pairs. These cells are attractive because the target is graft-localizing, immunologically consequential, and comparatively safe in the correct mismatch setting. By contrast, cytotoxic CAR-T or CAAR-T approaches aimed at donor-specific B cells, CD19-positive B cells, or BCMA-positive plasma cells remain more speculative in transplantation; their rationale is strengthened by autoimmune CAR-T experience but constrained by inflammatory toxicity, infection risk, and the difficulty of selectively deleting only alloreactive humoral memory. Xenotransplantation adds a further design layer because the donor organ can itself be genome edited, but clinical experience remains early and does not yet establish durable organ replacement. The central thesis is therefore deliberately modest: CAR-engineered cells may help move transplantation from generalized immunosuppression toward graft-localized immunoregulation, but only if target selection, Treg lineage stability, manufacturing feasibility, immunosuppression compatibility, and long-term safety are solved together.