Advancing allogeneic transplantation through multi-donor, immunotherapy, and precision strategies

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) represents one of the earliest and most successful forms of cellular immunotherapy. However, its curative potential is fundamentally constrained by a classic immunological dilemma: the same donor-derived alloreactive immune responses that drive the life-saving graft-versus-leukemia (GvL) effect also mediate devastating graft-versus-host disease (GvHD). Achieving long-term transplant success hinges on our ability to selectively preserve GvL while limiting GvHD.

In recent years, allo-HSCT has transitioned from broad, protocol-driven clinical decisions to a nuanced, mechanism-based specialty. Delineating how donor characteristics, including age, HLA matching, and donor source, shape the donor-derived immune repertoire has opened new avenues for precision transplant immunology. This includes haploidentical and matched unrelated donors. Concurrently, the field has seen rapid progress in engineered cellular products designed to induce selective tolerance, as well as next-generation immune-monitoring tools that support individualized, pre-emptive therapeutic interventions.

This Research Topic aims to compile cutting-edge mechanistic and translational research exploring how GvHD can be controlled while preserving GvL. We focus on three core pillars:

1. Donor-Driven Shaping of Alloimmunity: Exploring how donor sources, including haploidentical, cord blood, and matched unrelated donors, generate distinct alloreactive T-cell, B-cell, NK-cell, and antibody dynamics, and how these affect clinical outcomes and immune tolerance.

2. Engineered Cellular Immunotherapies: Investigating innovative cellular strategies, including regulatory T cells (Tregs), veto cells, mesenchymal stromal cells (MSCs), and bioengineered or nano-encapsulated donor lymphocyte infusions (DLI), to selectively suppress alloreactivity while preserving GvL.

3. Precision Immune Monitoring and Predictive Biomarkers: Advancing the clinical translation of cellular, cytokine, and molecular signatures to monitor immune reconstitution, pre-empt GvHD or infectious complications, including CMV and EBV reactivation, and guide precision pre-emptive therapy.

By centering the discussion on the immunological mechanisms of alloreactivity rather than purely clinical hematology protocols, this topic seeks to provide a distinct, unified platform for translating basic transplant immunobiology into precision clinical strategies. We invite the submission of Original Research, Reviews, Mini-Reviews, and Perspective articles covering, but not limited to, the following subtopics:

• Mechanisms of the GvHD-GvL Axis: Fundamental biology of donor-derived T-cell, B-cell, and NK-cell alloreactivity, and how distinct donor platforms, including haploidentical, matched unrelated, and cord blood transplantation, shape this axis.

• Engineered Cellular Products for Selective Tolerance: Preclinical and clinical development of cellular therapies designed to control GvHD without compromising GvL, including Tregs, veto cells, virus-specific T cells, and genetically or chemically modified donor lymphocytes.

• Stromal and Microenvironmental Immunomodulation: The role of MSCs and other microenvironmental components in modulating transplant-related inflammation and alloreactivity.

• Biomarker-Guided Precision Intervention: Discovery, validation, and clinical application of cytokine profiles, immune subsets, and molecular signatures to predict, stratify, or pre-emptively treat GvHD, viral reactivation, or early relapse.

• Predictive Modeling of Alloimmune Complications: Development and validation of risk-scoring models that integrate clinical donor-recipient characteristics with biological parameters to guide post-transplant care.