Building tolerance: employing genome engineering toward universal Treg therapy

Following the 2025 Nobel Prize in Physiology or Medicine for the discovery of regulatory T cells (Tregs), a recent article in Nature Communications reports the generation of allogeneic, genome-edited Tregs engineered to evade immune rejection while retaining suppressive function. Through non-viral CRISPR deletion of B2M and CIITA and insertion of an HLA-E-B2M fusion, the authors produced hypo-immunogenic Tregs that persisted and promoted graft tolerance in humanized mice. In this News and Views, the promise and challenges of such universal "off-the-shelf" Tregs are discussed, emphasizing how genome engineering is reshaping Treg biology into a new era of programmable immune tolerance.