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 <i>DDR1</i> expression, genetic alterations, and its associations with immune cell infiltration and clinical outcomes. <i>DDR1</i> 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 <i>DDR1</i>-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.