Dual roles of DDR1 in stromal remodeling and immune escape: a regulator of the tumor immune microenvironment
TL;DR
The current understanding of DDR1 as a central regulator of the tumor immune microenvironment is synthesized and the translational potential and challenges of DDR1-targeting strategies to enhance cancer immunotherapy are discussed.
Abstract
The discoidin domain receptor 1 (DDR1) is a collagen-activated receptor tyrosine kinase that orchestrates multiple cellular processes and remodels the tumor immune microenvironment (TIME). Notably, DDR1 promotes immune exclusion predominantly through its extracellular domain, which regulates collagen fiber alignment to form a physical barrier that impedes cytotoxic T cell infiltration, a function independent of its kinase activity. Moreover, DDR1 mediates cancer cell adhesion, migration, and metabolic reprogramming, while modulating cancer-associated fibroblasts, macrophages, and neutrophils to establish an immunosuppressive niche. Recently, DDR1-targeting strategies have been in preclinical and early clinical development, including selective small-molecule inhibitors, monoclonal antibodies, antibody–drug conjugates, and proteolysis-targeting chimeras. Combining DDR1 inhibition with immune checkpoint blockade has demonstrated synergistic antitumor efficacy in preclinical models. This review synthesizes the current understanding of DDR1 as a central regulator of the TIME and discusses the translational potential and challenges of DDR1-targeting strategies to enhance cancer immunotherapy.