Given its intricate impact on malignancy, DKK1 has become a promising therapeutic target, with ongoing clinical trials investigating neutralizing antibodies such as DKN-01 to disrupt its oncogenic and immunosuppressive signaling. Understanding the context-dependent nature of DKK1 signaling remains essential for refining its application as both a biomarker and a component of emerging precision immunotherapy strategies. By prioritizing the literature from the last decade, this review characterizes DKK1 as a key mediator of tumor progression and immune reprogramming, while assessing its clinical potential as a biomarker and therapeutic target.

In vivo, GB22-45-2 showed a modest tumor growth inhibition (31.03%) that is significant (P = 0.0175), while DKN-01 did not reach significance, in the MKN-45-Balb/c-nude mouse model. Additionally, GB22-45-2 exhibited a satisfactory developability profile, including good thermal stability, low aggregation propensity, high structural integrity, and excellent stability under various stress conditions. In summary, these preclinical results suggest that GB22-45-2 is a potential therapeutic candidate for GC, laying the foundation for its future drug development.

P2, N=8, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting | N=60 --> 8

P2, N=247, Terminated, Leap Therapeutics, Inc. | Trial completion date: Dec 2025 --> Mar 2025 | Active, not recruiting --> Terminated; experimental treatment will not be more efficacious than its comparator in the primary endpoint of PFS

P2, N=188, Completed, Leap Therapeutics, Inc. | Active, not recruiting --> Completed | Trial completion date: Oct 2025 --> Jul 2025 | Trial primary completion date: Oct 2025 --> Jul 2025

The median OS was 8.2 months, median PFS 1.4 months, and DCR rate 34.8% in the overall population. Although exploratory, the results of this trial compare favorably against second-line benchmarks of Keynote-061 and RAINBOW and support the safety and tolerability of DKN-01 combined with tislelizumab.

P2, N=60, Recruiting, Shanghai Junshi Bioscience Co., Ltd. | Not yet recruiting --> Recruiting

P1/2, N=52, Active, not recruiting, Royal Marsden NHS Foundation Trust | Trial completion date: Sep 2025 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Mar 2025

P2, N=60, Not yet recruiting, Shanghai Junshi Bioscience Co., Ltd.

P2, N=56, Shanghai East Hospital; Shanghai East Hospital

P1/2, N=186, Recruiting, Shanghai Junshi Bioscience Co., Ltd. | Not yet recruiting --> Recruiting | Trial completion date: Apr 2026 --> Jan 2026

P2, N=37, Not yet recruiting, Shanghai East Hospital; Shanghai East Hospital