Extracellular DDR1 targeting remodels collagen-rich tumor stroma and local immunity
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Collagen-rich stroma can restrict immune-cell access and sustain immune exclusion in solid tumors, but strategies that directly target extracellular matrix-organizing receptors remain limited. Here, we develop cross-reactive nanobody–Fc proteins against extracellular discoidin domain receptor 1 (DDR1) and identify DDR1nb-3-Fc as a lead molecule with activity in immunocompetent mammary and pancreatic tumor models, including an orthotopic pancreatic model. Tumor control is accompanied by altered collagen architecture and remodeling of the intratumoral immune compartment rather than consistent direct tumor-cell growth inhibition. Single-cell profiling with mouse-level compositional and pseudobulk analyses reveals reproducible pathway-level remodeling of tumor-associated neutrophils, while Ly6G-positive cell depletion significantly modifies the antitumor effect of DDR1nb-3-Fc. These findings identify extracellular DDR1 as an actionable regulator of collagen-rich tumor stroma and support its targeting as a strategy to reshape the tumor microenvironment and promote tumor control.
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In brief
Huang et al. develop cross-reactive nanobody–Fc proteins targeting extracellular DDR1. In immunocompetent mammary and pancreatic tumor models, DDR1 targeting suppresses tumor growth alongside changes in collagen architecture and local immunity. Mouse-level transcriptomic analyses and Ly6G-directed perturbation reveal an additional neutrophil-associated component of the therapeutic response.
Highlights
Extracellular DDR1 targeting remodels collagen-rich tumor stroma
DDR1 nanobody–Fc suppresses mammary and pancreatic tumor growth
DDR1 targeting alters intratumoral lymphoid and neutrophil compartments
Ly6G-positive cells modify the response to DDR1nb-3-Fc
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Authors used HEK293-F from @cellosaurus.bsky.social in their study. Including #RRIDs will make this less ambiguous. SciScore made a table with this resource, see “Automated Services” module (download as csv, xml or #jats) #reproducibility #STMpublishing
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Extracellular DDR1 targeting remodels collagen-rich tumor stroma and local immunity #SingleCell 🧪🧬🖥️ https://www.biorxiv.org/content/10.64898/2026.10.29.762758v1
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Extracellular DDR1 targeting remodels collagen-rich tumor stroma and local immunity https://www.biorxiv.org/content/10.64898/2026.10.29.762758v1
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Extracellular DDR1 targeting remodels collagen-rich tumor stroma and local immunity https://www.biorxiv.org/content/10.64898/2026.10.29.762758v1
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