Frontiers in Immunology· 2026Q1· Review
Dual roles of DDR1 in stromal remodeling and immune escape: a regulator of the tumor immune microenvironment
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- Q1SCImago
- 2026year
Short summary
Discoidin domain receptor 1 (DDR1) remodels the tumor immune microenvironment by its extracellular domain, which aligns collagen fibers to physically block T cell infiltration, independent of its kinase activity.
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Key points
- DDR1's extracellular domain aligns collagen fibers, creating a physical barrier that excludes cytotoxic T cells from tumors.
- This collagen alignment function is independent of DDR1's kinase activity.
- DDR1 also reprograms cancer cell metabolism and influences stromal cells to create an immunosuppressive TIME.
- DDR1-targeting therapies, such as small-molecule inhibitors and antibodies, are in preclinical and early clinical development.
- Combining DDR1 inhibition with immune checkpoint blockade shows synergistic antitumor effects in preclinical models.
AI-generated from the title and abstract; the full text is not read.
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.
The authors' abstract, as published at the source. Frontiers in Immunology, 2026 · DOI ↗
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Immunology and AllergyMedicine