Targeting Immune Signaling Pathways in Graft-Versus-Host Disease; A Signaling-Centric Review of Future Therapeutic Strategies

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) and next-generation al-logeneic T cell therapies are curative options for hematologic malignancies, but their effi-cacy is often limited by graft-versus-host disease (GvHD), a complex syndrome resulting from dysregulated donor–host immune interactions. GvHD is mediated by interconnected signaling pathways that regulate T cell activation, metabolic and epigenetic program-ming, tissue-specific migration, stromal-immune interactions, and fibrotic remodeling. Therapeutic agents targeting key pathways, including ruxolitinib (JAK1/2), ibrutinib (BTK/ITK), and belumosudil (ROCK2), can modulate inflammatory responses while pre-serving graft-versus-tumor (GvT) activity. Emerging technologies, such as CRISPR-based genome editing, single-cell and spatial multi-omics, and AI-driven network modeling, enable patient-specific mapping of signaling hierarchies, prediction of disease trajectories, and identification of actionable targets. Integration of these approaches supports precise modulation of immune circuits, offering alternatives to broad immunosuppression. These insights provide a framework for next-generation, individualized interventions that pro-mote durable immune tolerance without compromising anti-tumor immunity and high-light rational combination strategies to improve outcomes in allo-HSCT and allogeneic T cell therapies.