2. Academic Validation
  3. Syndecan-1-targeted therapeutic antibody impairs macropinocytosis and elicits antitumor immunity in pancreatic cancer

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

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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