Extracellular DDR1 targeting remodels collagen-rich tumor stroma and local immunity

Abstract

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.