Thymus regeneration therapies: entering a new era

The function of the thymus, essential for T cell development, declines sharply with age. Genetic defects that disrupt thymic organogenesis or function lead to profound immunodeficiency and autoimmunity. Allogeneic thymus transplantation for congenital athymia, the only existing thymus replacement therapy, provides proof of concept for T cell reconstitution but remains constrained by donor availability and Human Leukocyte Antigen (HLA) mismatch. Advances in single-cell biology and stem cell engineering now make scalable thymus regeneration an attainable goal. In particular, induced pluripotent stem cell-derived thymic epithelial cells could restore endogenous T cell development and immune tolerance in an HLA-compatible manner. We propose that the thymus is uniquely suited for stem cell-based regeneration, with the potential to transform the treatment of immune deficiency, transplantation, cancer, autoimmunity, and aging itself.