Targeted DDR1 Treatment Strategy Enhances PD-1 Immunotherapy Efficacy against Gastric Cancer.

Despite advances in immunotherapy, many patients with advanced gastric cancer (GC) remain refractory. Discoidin domain receptor 1 (DDR1) was identified as a key mediator of tumor-stroma interactions and immunosuppression. Multiomics analysis associated high DDR1 expression with poor prognosis and an immunosuppressive microenvironment. Genetic DDR1 knockdown inhibited tumor progression, leading to the development of a DDR1-targeting monoclonal antibody (mAb). In murine models, this anti-DDR1 mAb synergized with anti-PD-1 therapy, suppressing tumor growth and improving survival. Mechanistically, the mAb binds the DDR1 DS-DS-like-EJM domain, competitively inhibiting collagen I interaction and blocking the Col1-DDR1-ERK pathway. It exerts dual immune-activating effects by inducing ADCC/CDC and upregulating CCL3/CXCL11 to enhance CD8+ T cell recruitment and cytotoxicity. Thus, DDR1 inhibition presents a multimodal strategy that suppresses tumor signaling and converts immunologically "cold" tumors, supporting its combination with PD-1 blockade as a promising GC treatment.