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

Yonggang Tian1, Jun Wang2, Long Qin3

  • 1Department of Gastroenterology, The Second Clinical Medical College of Lanzhou University, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, China.

Journal of Medicinal Chemistry
|October 27, 2025
PubMed

Insights

Targeting Discoidin domain receptor 1 (DDR1) with a novel antibody overcomes immunotherapy resistance in gastric cancer. This approach inhibits tumor growth and enhances anti-PD-1 therapy effectiveness by modulating the tumor microenvironment.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Advanced gastric cancer (GC) often shows resistance to current immunotherapy treatments.
  • Discoidin domain receptor 1 (DDR1) plays a crucial role in tumor-stroma interactions and creates an immunosuppressive tumor microenvironment.
  • High DDR1 expression correlates with poor prognosis in gastric cancer patients.

Purpose of the Study:

  • To investigate the therapeutic potential of targeting DDR1 in advanced gastric cancer.
  • To develop and evaluate a DDR1-targeting monoclonal antibody (mAb) for gastric cancer treatment.
  • To elucidate the mechanisms by which DDR1 inhibition impacts tumor progression and the immune microenvironment.

Main Methods:

  • Multiomics analysis to associate DDR1 expression with GC prognosis and immunosuppression.
  • Genetic knockdown of DDR1 to assess its role in tumor progression.
  • Development of a DDR1-targeting monoclonal antibody (mAb).
  • In vivo studies using murine models to evaluate the efficacy of anti-DDR1 mAb in combination with anti-PD-1 therapy.
  • Mechanistic studies to determine how the mAb interacts with DDR1 and affects downstream signaling pathways (Col1-DDR1-ERK) and immune cell recruitment (CD8+ T cells).

Main Results:

  • High DDR1 expression was linked to poor prognosis and an immunosuppressive tumor microenvironment in GC.
  • Genetic DDR1 knockdown demonstrated its importance in inhibiting tumor progression.
  • The anti-DDR1 mAb synergized with anti-PD-1 therapy in murine models, significantly suppressing tumor growth and improving survival.
  • The mAb binds to the DDR1 DS-DS-like-EJM domain, inhibiting collagen I interaction and blocking the Col1-DDR1-ERK pathway.
  • The mAb demonstrated dual immune-activating effects, including antibody-dependent cellular cytotoxicity (ADCC)/complement-dependent cytotoxicity (CDC) and enhanced recruitment/cytotoxicity of CD8+ T cells via CCL3/CXCL11 upregulation.

Conclusions:

  • DDR1 inhibition is a promising multimodal strategy for gastric cancer treatment.
  • Targeting DDR1 can convert immunologically "cold" tumors into more responsive ones.
  • The combination of DDR1 blockade with PD-1 inhibitors represents a novel and potentially effective therapeutic approach for advanced gastric cancer.

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