Bridging Innate and Adaptive Immunity: Understanding and Targeting the Complement System in GVHD Pathogenesis and...

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a cornerstone curative strategy for patients with high-risk hematological malignancies. However, its therapeutic efficacy is often compromised by graft-versus-host disease (GVHD), a potentially life-threatening complication driven by the dysregulated immune response of donor-derived cells against host tissues. The current first-line management of GVHD primarily relies on glucocorticoids and broad-spectrum immunosuppressants; nevertheless, 30% to 50% of patients develop steroid-refractory GVHD or suffer from serious treatment-related toxicities, underscoring the urgent need for more precise and effective therapeutic approaches. In recent years, the complement system-traditionally regarded as a key component of innate immunity-has emerged as a critical modulator of adaptive immune responses in GVHD pathogenesis. Increasing evidence implicates the complement cascade, particularly the C3a/C5a-C3aR/C5aR signaling axis, in promoting Th1/Th17 polarization and effector T cell infiltration, while concurrently impairing regulatory T cell (Treg) function, thereby exacerbating immune dysregulation and tissue injury. This review provides a comprehensive overview of the complement system's role in GVHD, focusing on 2 key aspects: (1) the molecular mechanisms through which complement components influence T and B cell activation and contribute to target organ damage; and (2) recent preclinical advances in complement-targeted therapeutic strategies. By integrating current findings, we aim to establish a theoretical framework for the development of safer and more effective complement-directed therapies, and to explore their potential in achieving personalized GVHD management.