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

Collagen-rich tumor stroma can hinder immune cell access and maintain immune exclusion in solid tumors, but direct targeting strategies for extracellular matrix organizing receptors like extracellular discoidin domain receptor 1 (DDR1) are scarce. Researchers have now developed cross-reactive nanobody Fc proteins against DDR1, with DDR1nb 3 Fc emerging as a promising lead molecule.

This molecule demonstrated activity in immunocompetent models of mammary and pancreatic tumors, including an orthotopic pancreatic tumor model. The observed tumor control was not due to consistent direct inhibition of tumor-cell growth, but rather, alterations in collagen architecture and remodeling of the intratumoral immune compartment.

Single-cell profiling using mouse level compositional and pseudobulk analyses revealed reproducible pathway-level remodeling of tumor-associated neutrophils. The study also found that Ly6G-positive cell depletion significantly influenced the antitumor effect of DDR1nb 3 Fc. These findings highlight 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.