Harnessing MSCs plasticity: mechanisms and determinants of bidirectional immune regulation in stem-cell-based immunotherapy

Mesenchymal stem cells (MSCs) have been extensively investigated and applied in autoimmune and inflammatory diseases owing to their tissue-repair capacity and immunomodulatory properties, and they hold significant promise in cellular immunotherapy. However, therapeutic outcomes of stem-cell-based immunotherapy can be inconsistent, because the immunomodulatory effects of MSCs may undergo dynamic shifts in response to changes in the microenvironment. Research has shown that the inflammatory state of the tissue microenvironment affects the tendency of MSCs to regulate immunity. Under highly inflammatory conditions, MSCs tend to exert immunosuppressive functions, while under low inflammatory conditions, MSCs tend to exhibit immune support. In addition, the physical culture method, pretreatment conditions, and tissue source of stem cells all affect the direction of their immune regulation. Therefore, gaining a deep understanding of the immune regulatory mechanisms of MSCs and their influencing factors is crucial for optimizing their application in stem cell immunotherapy and improving treatment outcomes. This review first explores the potential factors influencing MSCs’ bidirectional immune regulation, then discusses the mechanisms underlying the immunosupportive and immunosuppressive effects of MSCs, and finally briefly describes the role of MSCs’ bidirectional immune regulation function in disease treatment.