Immunomodulatory properties of umbilical cord mesenchymal stromal cells in immune disorders: immunoregulatory functions, therapeutic progress, and engineering strategies for enhanced efficacy.

Immune disorders remain a major global health challenge, as conventional immunosuppressive therapies are often hampered by severe side effects and unsatisfactory long-term efficacy. Umbilical cord-derived mesenchymal stromal cells (UC-MSCs) have emerged as a promising therapeutic modality for various immune disorders and balance immune homeostasis by regulating various immune cells and secreting anti-inflammatory mediators. We systematically review and synthesize preclinical and clinical evidence supporting UC-MSC treatment for major immune diseases, with graft-versus-host disease, systemic lupus erythematosus, inflammatory bowel disease, and rheumatoid arthritis being prime examples. Despite the promising therapeutic outcomes, therapeutic efficacy and large-scale clinical manufacturing of UC-MSC therapies are constrained by multiple challenges. This review also systematically examines the major translational bottlenecks for UC-MSCs in treating immune disorders, including cellular heterogeneity, non-uniform preparation standards, impaired homing and biodistribution, and insufficient long-term safety data. Finally, two main avenues for enhancing UC-MSC therapeutic potential are summarized, including optimized culture strategies, such as hypoxic preconditioning, cytokine priming, and three-dimensional spheroid culture, and genetic engineering. It is hoped that we will be able to gain a deeper understanding of the development of stable and scalable UC-MSC interventions for immune diseases.