Syndecan-1-targeted therapeutic antibody impairs macropinocytosis and elicits antitumor immunity in pancreatic cancer

  • Cell Rep Med. 2026 Feb 17;7(2):102613. doi: 10.1016/j.xcrm.2026.102613.
Zecheng Yang  1 ,  Madelaine S Theardy  1 ,  Shuaitong Chen  1 ,  Yongkun Wei  2 ,  Mitsunobu Takeda  3 ,  Yue Zeng  1 ,  Xiaofei Wang  4 ,  Jun Yao  2 ,  Jennifer Li  4 ,  Prapassorn Thirasastr  5 ,  Jangho Park  1 ,  Yangxi Zheng  6 ,  Long T Vien  7 ,  Khalida M Wani  4 ,  Huamin Wang  8 ,  Sisi Gao  9 ,  Tim Heffernan  9 ,  Lawrence Kwong  1 ,  Ignacio I Wistuba  1 ,  Laura Bover  7 ,  Giulio F Draetta  7 ,  Haoqiang Ying  10 ,  Wantong Yao  11
Affiliations
  • 1. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA.
  • 2. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 3. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 4. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 5. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 6. The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA; Department of Stem Cell Transplantation & Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 7. The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 8. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA; Department of Anatomical Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 9. Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION), The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 10. The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA; Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: [email protected].
  • 11. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA; Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: [email protected].
PMID: 41707651 DOI: 10.1016/j.xcrm.2026.102613
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; immunotherapy; macropinocytosis; natural killer cells; pancreatic cancer; therapeutic antibody.
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