SSTN(IV), a syndecan-1-targeting peptide chimera, reverses immune suppression and inhibits myeloma progression
Summary
Despite therapeutic advances, multiple myeloma (MM) remains incurable, largely due to relapse and the emergence of drug resistance driven by clonal evolution and alterations in the bone marrow (BM) microenvironment that support tumor survival. This highlights the need for novel therapeutics targeting both tumor cells and the supportive BM niche, particularly for patients with relapsed/refractory MM. Syndecan-1 (Sdc1/CD138), a heparan sulfate proteoglycan, is abundantly expressed on both th
Content
# SSTN(IV), a syndecan-1-targeting peptide chimera, reverses immune suppression and inhibits myeloma progression
*Published: 2026 May 12*
Despite therapeutic advances, multiple myeloma (MM) remains incurable, largely
due to relapse and the emergence of drug resistance driven by clonal evolution
and alterations in the bone marrow (BM) microenvironment that support tumor
survival. This highlights the need for novel therapeutics targeting both tumor
cells and the supportive BM niche, particularly for patients with
relapsed/refractory MM. Syndecan-1 (Sdc1/CD138), a heparan sulfate proteoglycan,
is abundantly expressed on both the surface of myeloma cells and within the MM
microenvironment. It plays a critical role in MM pathogenesis by promoting cell
survival, angiogenesis, and immune evasion. This study investigates a novel
chimeric peptide, SSTNIV, which disrupts Sdc1-mediated mechanisms to inhibit MM
progression. Using murine VQ models of advanced MM, we evaluated the effects of
SSTNIV on tumor growth, metastasis, and the tumor microenvironment. Our results
demonstrate that SSTNIV effectively inhibits MM cell invasion, induces
apoptosis, and reverses immune suppression in vitro. Importantly, in VQ mice,
SSTNIV significantly prolonged survival, reduced tumor burden, and improved BM
cellularity. When combined with the frontline MM chemotherapy agent bortezomib,
SSTNIV conferred the greatest survival benefit, substantially reducing MM cells
in BM, alleviating extramedullary disease, and restoring hematopoiesis.
Furthermore, human BM microarray analysis using proximity ligation assay
confirmed that Sdc1 forms complexes with receptor tyrosine kinases and integrins
in human MM tumors targeted by SSTNIV, but not in normal BM. These findings
highlight SSTNIV's potent anti-myeloma activity and support its potential as a
promising therapeutic strategy for advanced and relapsed/refractory MM.
DOI: 10.1038/s41392-026-02709-1