Trichostatin A Sensitizes Tumor Cells to Apoptosis Induced by Soluble Trimeric <scp>TRAIL</scp> ‐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.