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Syndecan-1-targeted therapeutic antibody inhibits macropinocytosis and induces antitumor immunity in pancreatic cancer

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies, with a 5-year survival rate of just 13%. While the development and early clinical use of small molecules targeting oncogenic KRAS mutations, key drivers of PDAC, have shown promise, resistance to these targeted therapies remains a significant challenge. We recently identified Syndecan-1 (SDC1), a highly expressed heparan sulfate proteoglycan, as a critical KRAS effector protein that promotes nutrient salvage and tumor growth. Here, we report the development of a human-specific monoclonal antibody (anti-SDC1 mAb) that inhibits PDAC cell proliferation in vitro and suppresses PDAC tumor growth in vivo. Mechanistically, anti-SDC1 mAb blocks macropinocytosis and induces antibody-dependent cellular cytotoxicity (ADCC). In vivo, anti-SDC1 mAb synergizes with standard chemotherapy, KRAS* inhibitors, and immunotherapies, resulting in tumor regression and near-complete response. These findings highlight anti-SDC1 mAb as a promising therapeutic strategy for PDAC and potentially other KRAS* and SDC1-driven tumors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE311267 | GEO | 2025/12/02

REPOSITORIES: GEO

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