Cell death pathways in graft-versus-host disease

Regulated cell death, including apoptosis, necroptosis, and pyroptosis, as well as cell death arising from disrupted cellular homeostasis, such as ferroptosis and dysregulated autophagy, is implicated in cancer, autoimmunity, and transplantation biology. Graft-versus-host disease (GVHD), a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation, is driven by donor T-cell recognition of host alloantigens and effector response, leading to extensive tissue injury. Apoptotic pathways have been well studied in GVHD, and targeting apoptosis has shown therapeutic benefit. Emerging forms of cell death are now recognized to regulate immune and non-immune cells, providing new mechanistic insights into GVHD. Manipulating these pathways offers opportunities to alleviate GVHD through eliminating pathogenic alloreactive T cells or enhancing the survival of protective cell populations, such as regulatory T cells, innate lymphoid cells, and intestinal epithelial cells. We summarize recent advances on how diverse cell death pathways shape GVHD pathogenesis and their therapeutic implications.