DDR1 Drives Collagen Remodeling and Immune Exclusion: Pan-Cancer Insights and Therapeutic Targeting in Pancreatic Ductal Adenocarcinoma.

Discoidin domain receptor 1 (DDR1), a collagen-binding receptor tyrosine kinase, plays a key role in extracellular matrix remodeling, tumor progression, and immune evasion. However, DDR1's comprehensive role across diverse cancers and its therapeutic potential in immune-resistant tumors remain poorly defined. We performed a pan-cancer analysis integrating bulk transcriptomic datasets, single-cell RNA sequencing, and pathway enrichment to evaluate DDR1 expression, genetic alterations, and its associations with immune cell infiltration and clinical outcomes. DDR1 was consistently overexpressed in 21 cancer types, correlating with poor prognosis and reduced immune cell infiltration. Mechanistically, DDR1 promoted collagen remodeling, immune exclusion, and upregulated immunosuppressive pathways. Single-cell analysis in pancreatic ductal adenocarcinoma (PDAC) revealed DDR1-high ductal cells associated with reduced cytotoxic T cell infiltration and increased regulatory T cell populations. Therapeutic blockade of DDR1 in an immunocompetent KPC mouse model of PDAC disrupted collagen architecture, enhanced CD8+ T cell infiltration, and improved responses to chemotherapy, highlighting a direct link between DDR1 inhibition and immune reactivation. These findings establish DDR1 as a key mediator of collagen-driven immune resistance and a promising therapeutic target for overcoming immune exclusion, especially in PDAC and other collagen-rich solid tumors.