Immune signaling networks in graft-versus-host disease: From mechanism to precision therapeutic targeting

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) and emerging allogeneic T cell therapies offer curative potential for hematologic malignancies, but their benefits remain constrained by graft-versus-host disease (GvHD). Although multiple signaling pathways contribute to GvHD, their effects are determined by dynamic interactions among immune cell subsets, tissue compartments, and disease stages rather than by isolated pathway activation. Here, we provide a network centered synthesis of major GvHD signaling pathways, including JAK/STAT, BTK/ITK, PI3K/AKT/mTOR, NF-κB, NFAT, MAPK, and Notch, with emphasis on pathway crosstalk, feedback, cellular and tissue context, and the distinct yet overlapping biology of acute and chronic GvHD. We further examine how network connectivity and context dependent signaling influence therapeutic responses and the challenge of suppressing pathogenic alloimmunity while preserving beneficial graft-versus-leukemia (GvL) activity. This framework highlights GvHD as a dynamically interconnected signaling disorder and provides a context aware basis for interpreting pathway directed therapies according to cellular context, disease stage, and the level of clinical evidence supporting each therapeutic approach.