CCL22-engineered MSCs modulate immune crosstalk to shape an immunosuppressive microenvironment for graft protection

Mesenchymal stem cells (MSCs) hold great potential for cell-based immunotherapy owing to their potent immunomodulatory capabilities, yet improving their targeted immunosuppressive effects remains challenging. In this study, we genetically engineered bone marrow-derived MSCs to overexpress the chemokine CCL22 (CCL22-OE MSCs) to establish a tolerogenic local microenvironment. We found that CCL22-OE MSCs stably secreted functional CCL22 while maintaining their fundamental biological characteristics. In a mouse model of allogeneic islet transplantation, CCL22-OE MSCs significantly reshaped the immune microenvironment of the grafts. Single-cell RNA sequencing and functional assays revealed that engineered MSCs promoted the accumulation of regulatory T cells (Tregs) and induced the polarization of immunosuppressive TREM2⁺ macrophages. Mechanistically, CCL22-OE MSCs recruited Tregs and enhanced their immunosuppressive function, which in turn educated macrophages toward a tolerogenic TREM2⁺ phenotype. These TREM2⁺ macrophages further amplified local immunosuppression through paracrine and cell-contact–dependent signaling pathways, forming a positive immunoregulatory crosstalk loop. Functionally, pretreatment with CCL22-OE MSCs markedly prolonged allogeneic islet graft survival and improved metabolic control in diabetic mice. Our results demonstrate that CCL22-engineered MSCs can establish a robust local immunosuppressive network by coordinating Treg and TREM2⁺ macrophage crosstalk, representing a novel and effective strategy to alleviate immune rejection in cell transplantation.