As part of the conditioning regimen, irradiation or chemotherapy lead to tissue damage and barrier dysfunction of the intestinal epithelia, which is further exacerbated by alloreactive donor T cells. Henden et al propose here a dual mechanism for IFN-λ in mitigating acute intestinal GVHD, acting as: (1) a critical proliferative factor for Lgr5⁺ ISCs, thereby restoring barrier function and regeneration of intestinal epithelial cells (IECs), and (2) a crucial mediator of recipient NK-cell function, thereby ameliorating alloreactive donor T-cell responses.