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This communication occurs through a plethora of mechanisms, including the release of cytokines and small extracellular vesicles (sEVs). The PDZ protein syntenin is a master regulator of intercellular communication, in particular via sEVs. In this study, we aimed to explore whether targeting syntenin, by genetic alteration or pharmacological inhibition, can disrupt BMSC\u2013MM crosstalk, thereby rendering the MM cells more sensitive to therapy. We found that syntenin (SDCBP) is highly expressed in inflammatory BMSC of MM patients and that its expression in BM aspirates correlates with poor patient survival. Using in vitro models, we established that knockout of syntenin in BMSC alters their secretome and abolishes BMSC\u2010induced bortezomib resistance of MM cells via regulation of STAT3, MAPK, and AKT\u2010mTOR pathways. Pharmacological inhibition of syntenin decreases syntenin and IL\u20106 sorting into BMSC sEVs and enhances bortezomib\u2010induced MM cell death. Finally, we validated the therapeutic added value of syntenin inhibition in combination with bortezomib in vivo, using the 5TGM1 MM mouse model. In conclusion, our findings show that syntenin supports the secretion of pro\u2010tumoral factors by BMSCs and qualifies as a possible novel therapeutic target in MM.<\/jats:p>","DOI":"10.1002\/hem3.70197","type":"journal-article","created":{"date-parts":[[2025,8,18]],"date-time":"2025-08-18T09:04:58Z","timestamp":1755507898000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Syntenin inhibition impairs stroma\u2010tumor communication in multiple myeloma and improves bortezomib treatment efficiency"],"prefix":"10.1002","volume":"9","author":[{"given":"Chenggong","family":"Tu","sequence":"first","affiliation":[{"name":"Translational Oncology Research Center, Team Hematology and Immunology Vrije Universiteit Brussel Brussels Belgium"},{"name":"Laboratory for Extracellular Vesicle Research, Department of Human Genetics KULeuven Leuven 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