Ewing sarcoma (EWS) is the second most frequent pediatric malignant bone tumor. EWS patients have not seen any major therapeutic progress in the last 30 years, in particular in the case of metastatic disease, which requires new therapeutic strategies. The pro-apoptotic cytokine TNF-Related Apoptosis Inducing Ligand (TRAIL) can selectively kill tumor cells while sparing normal cells, making it a promising therapeutic tool in several types of cancer. However, certain EWS cell lines appear resistant to recombinant human (rh) TRAIL-induced apoptosis. We therefore hypothesized that a TRAIL presentation at the surface of the carrier cells might overcome this resistance and trigger apoptosis. For this purpose, human adipose mesenchymal stromal/stem cells (MSC) transfected in a stable manner to express full-length human TRAIL were co-cultured with several human EWS cell lines, inducing apoptosis by cell-to-cell contact even in cell lines initially resistant to rhTRAIL or AMG655, an antibody agonist to the death receptor, DR5. In vivo, TRAIL delivered by MSCs was able to counteract tumor progression in two orthotopic models of Ewing sarcoma, associated with caspase activation, indicating that a cell-based delivery of a potent apoptosis-inducing factor could be relevant in EWS. Ewing sarcoma (EWS), the second most common malignant bone tumor in pediatric patients after osteosarcoma, is a rare form of cancer. It is highly metastatic and causes serious disruption to bone remodeling. EWS is identified by a chromo-somal translocation between the EWS gene on chromosome 22 and a member of the ETS transcription factor family, more often FLI1 on chromosome 11, leading to production of a fusion protein which behaves like an aberrant transcription factor. 1 The resulting fusion protein, EWS-FLI1, directly or indirectly modulates the expression of many genes, altering several cell functions such as cell cycle (by targeting p21/CDKN1A, Cyclin D and E, p57/KIP2, TGFa-, IGF-, or MAPK signaling pathways) or apoptosis (by targeting capase3 and members of the TNFa, IGF-1 and TGFb signaling pathways). 2 Transformed EWS cells appear as small, round and undifferentiated, and they are involved in major disruption of bone structure, with severe osteolytic lesions. The current therapeutic approach consists of surgery, neoad-juvant and adjuvant chemotherapy, and in some cases radiother-apy. The 5-year survival rate has barely changed in the past 30 years, and remains at around 70% for localized forms. 3 However, the rate falls drastically to around 20% for groups of metastatic patients or poor responders to chemotherapy. New avenues of research have been opened by using TNF-Related Apoptosis Inducing Ligand (TRAIL), a pro-apoptotic cytokine from the TNF superfamily. TRAIL can bind to five receptors: two death receptors—TRAIL-R1 (Death Receptor 4: DR4) and TRAIL-R2 (DR5)—two decoy receptors that do not transmit the death signal but that can confer resistance toward TRAIL-induced apoptosis-TRAIL-R3 (Decoy Receptor 1: DcR1) and TRAIL-R4 (DcR2)—and the soluble osteoprotegerin (OPG). TRAIL, by binding to DR4 and DR5, is able to induce apoptosis of tumor cells by activating the recruitment and cleavage of pro-caspase