Mesenchymal stem cell-mediated delivery boosts the efficacy of suicide gene therapy based on retroviral replicating vectors in peritoneally disseminated cancer

Abstract Retroviral replicating vectors (RRVs) hold promise for cancer gene therapy but face limitations due to their relatively low titers and susceptibility to inactivation by body fluids, limiting their application to intratumoral delivery. To overcome these challenges and target metastatic cancers, we investigated the use of tumor-homing mesenchymal stem cells (MSCs) as RRV carriers in a clinically relevant model of malignant peritoneal mesothelioma. MSCs derived from adipose tissue, bone marrow, and umbilical cord demonstrated significant migration toward mesothelioma cells and were permissive to RRV infection and production. MSCs transferred RRVs to tumor cells more effectively in direct co-culture than in Transwell assays. Using peritoneally disseminated cancer models, we confirmed that MSCs enhanced RRV transfer, even under ascites-mimicking conditions. In vivo biomolecular imaging and flow cytometry revealed markedly reduced RRV transduction under ascites conditions; however, MSC/RRV delivery significantly enhanced intratumoral viral transmission. Furthermore, while both direct RRV and MSC/RRV treatments were effective in non-ascites models, MSC/RRV delivery achieved superior antitumor efficacy in ascites-mimicking models, resulting in robust tumor suppression and prolonged survival. These findings highlight the potential of MSCs to overcome the limitations of RRV and suggest that MSC-based RRV-mediated suicide gene therapy represents a promising strategy for peritoneally disseminated cancers complicated by cancerous ascites.