Engineered mesenchymal stem cells expressing CXCR4 and LIGHT enhance Anti-Tumor activity in a subcutaneous gastric cancer xenograft model

Gastric cancer remains a leading cause of cancer-related mortality, with limited treatment options and a poor prognosis. Mesenchymal stem cells (MSCs) possess inherent tumor-homing ability but exhibit modest efficacy against solid tumors. Enhancing both tumor targeting and immune activation through genetic modification may improve the therapeutic potential of these approaches. To evaluate the anti-cancer efficacy of human umbilical cord–derived MSCs (HUC-MSCs) genetically modified to co-express C-X-C chemokine receptor type 4 (CXCR4) and TNFSF14 (LIGHT) against gastric cancer in vitro and in vivo. HUC-MSCs were transduced via lentiviral vectors to generate dual-gene–engineered Tg-HUC-MSCs. In vitro, their effects on HGC-27 gastric cancer cells were assessed using the scratch wound migration assay and Annexin V/PI apoptosis analysis. In vivo, BALB/c nude mice bearing subcutaneous HGC-27 xenografts were treated with Tg-HUC-MSCs, unmodified HUC-MSCs, or a control. Tumor growth was monitored by caliper measurements. Excised tumors were analyzed histologically with hematoxylin–eosin staining and by Ki-67 immunohistochemistry. Tg-HUC-MSCs significantly inhibited HGC-27 cell migration and induced higher apoptosis rates than unmodified HUC-MSCs in vitro (p < 0.001). In vivo, Tg-HUC-MSCs markedly reduced tumor volume, increased necrotic areas, and decreased Ki-67 proliferation indices compared to controls (p < 0.001). Elevated CXCR4 and LIGHT expression correlated with improved tumor targeting and enhanced immune-mediated tumor cell killing. Dual-gene–engineered HUC-MSCs (CXCR4 + TNFSF14) demonstrated superior tumor-homing and anti-cancer activity against gastric cancer cells in vitro and in vivo, representing a promising cell-based therapeutic strategy for solid tumors.