Syndecan-1-Targeted Therapeutic Antibody Impairs Macropinocytosis and Elicits Antitumor Immunity in Pancreatic Cancer

Authors

Zecheng Yang
Madelaine S Theardy
Shuaitong Chen
Yongkun Wei
Mitsunobu Takeda
Yue Zeng
Xiaofei Wang
Jun Yao
Jennifer Li
Prapassorn Thirasastr
Jangho Park
Yangxi Zheng
Long T Vien
Khalida M Wani
Huamin Wang
Sisi Gao
Tim Heffernan
Lawrence Kwong
Ignacio I Wistuba
Laura Bover
Giulio F Draetta
Haoqiang Ying
Wantong Yao

Language

English

Publication Date

2-17-2026

Journal

Cell Reports Medicine

DOI

10.1016/j.xcrm.2026.102613

PMID

41707651

PMCID

PMC12923971

PubMedCentral® Posted Date

2-17-2026

PubMedCentral® Full Text Version

Post-print

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, the 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 the anti-SDC1 mAb as a promising therapeutic strategy for PDAC and potentially other KRAS∗ and SDC1-driven tumors.

Keywords

Syndecan-1, Humans, Pancreatic Neoplasms, Pinocytosis, Animals, Cell Line, Tumor, Carcinoma, Pancreatic Ductal, Mice, Antibodies, Monoclonal, Cell Proliferation, Antibody-Dependent Cell Cytotoxicity, Proto-Oncogene Proteins p21(ras), Xenograft Model Antitumor Assays, Female, Syndecan-1, therapeutic antibody, immunotherapy, natural killer cells, macropinocytosis, pancreatic cancer

Published Open-Access

yes

Recommended Citation

Yang, Zecheng; Theardy, Madelaine S; Chen, Shuaitong; et al., "Syndecan-1-Targeted Therapeutic Antibody Impairs Macropinocytosis and Elicits Antitumor Immunity in Pancreatic Cancer" (2026). Faculty, Staff and Student Publications. 6036.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6036