Faculty, Staff and Student Publications
Language
English
Publication Date
11-5-2025
Journal
npj Breast Cancer
DOI
10.1038/s41523-025-00843-7
PMID
41188249
PMCID
PMC12586714
PubMedCentral® Posted Date
11-5-2025
PubMedCentral® Full Text Version
Post-print
Abstract
Gangliosides are acidic glycosphingolipids involved in cell-adhesion, signal-transduction and tumor progression. GD3 synthase (GD3S/ST8SIA1), a key enzyme in ganglioside biosynthesis, is upregulated in many cancers, including GD2+ breast cancer stem-like cells (BCSCs) in triple-negative breast cancer (TNBC). Here, we demonstrated the immunomodulatory role of GD3S and identified a fully humanized anti-GD2 antibody, naxitamab, as a therapeutic tool to target GD3S/GD2+ breast tumors. GD3S expression correlates with immune-checkpoint activation and reduced immune infiltration. Ectopic overexpression of GD3S suppressed macrophage-mediated phagocytosis and NK or T cell-induced cell death in BC cells. Lipidomic analysis identified GD2 as the major effector ganglioside altered upon GD3S overexpression in TNBC cells. Moreover, naxitamab treatment enhanced macrophage-mediated phagocytosis and NK cell-mediated cytotoxicity and inhibited tumor growth in a TNBC patient-derived xenograft model. Our findings highlight GD3S-driven immunosuppression and provide proof-of-concept that naxitamab, with activated immune cells, reverses this effect, revealing its therapeutic potential in treating GD2+ BC.
Keywords
Breast cancer, Cancer immunotherapy, Targeted therapies, Cancer stem cells
Published Open-Access
yes
Recommended Citation
Anand, Vivek; Oderinde, Bolutyfe; Siddiqui, Maryam; et al., "Targeting GD2 With Naxitamab Overcomes GD3 Synthase-Driven Immune Suppression in Triple-Negative Breast Cancer" (2025). Faculty, Staff and Student Publications. 5275.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5275
Graphical Abstract
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