Trichostatin A Sensitizes Tumor Cells to Apoptosis Induced by Soluble Trimeric TRAIL ‐Expressing Human Mesenchymal Stromal Cells

Mesenchymal stromal cells (MSCs) are promising vehicles for delivering therapeutic agents to tumors, as a result of their tumor‐homing ability. This study aimed to develop MSCs expressing a trimeric soluble form of tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL), which was enhanced by incorporating an isoleucine zipper (SCZT), to improve apoptosis‐inducing efficacy. Because some cancer cells are resistant to TRAIL, we also investigated the effects of combining SCZT‐expressing MSCs with trichostatin A (TSA), a histone deacetylase inhibitor that enhances the expression of TRAIL death receptors (DR4/DR5) in tumor cells. TSA increased TRAIL sensitivity in resistant tumor cells in vitro by upregulating DR5, leading to enhanced caspase‐8 activation and tumor cell death. MSCs accumulated at tumor sites in vivo, and the combination of SCZT‐MSCs and TSA significantly suppressed tumor growth in both TRAIL‐sensitive and TRAIL‐resistant mouse models. Notably, this combination led to complete tumor regression in some TRAIL‐resistant tumors. These in vivo findings indicate that efficient tumor targeting by MSCs is crucial for achieving therapeutic efficacy, especially in TRAIL‐resistant tumors. Overall, our results demonstrate that co‐treatment with TSA enhances the antitumor effect of TRAIL‐expressing MSCs, offering a potential strategy to overcome TRAIL resistance and improve MSC‐based cancer therapies.