Click chemistry reverses tumour drug resistance in vivo
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A Nature study demonstrates that modular in vivo ligation of therapeutic antibodies to antibody–drug conjugates via bioorthogonal click chemistry enhances antitumour activity in heterogeneous and treatment-resistant tumours. The approach reverses drug resistance by enabling targeted delivery of cytotoxic payloads directly to cancer cells. The findings suggest a new strategy for overcoming tumour heterogeneity and acquired resistance.
The Mechanism
Researchers developed a modular system that uses bioorthogonal click chemistry to ligate clinically used therapeutic antibodies to antibody–drug conjugates (ADCs) directly in vivo. This in situ ligation allows the ADC to deliver a cytotoxic payload specifically to cancer cells expressing the target antigen. The method was tested in mouse models of heterogeneous and treatment-resistant tumours, where it showed enhanced antitumour activity compared to traditional ADCs.
Key Results
In xenograft models of drug-resistant breast and lung cancer, the click-chemistry approach reduced tumour volume by up to 80% over 30 days, while conventional ADCs achieved only 30% reduction. The treatment also prevented the emergence of resistant clones in 70% of treated mice. The study, published in Nature on 15 July 2026, involved researchers from Stanford University and the University of California, San Francisco.
What's Next
The team plans to test the approach in larger animal models and eventually in human clinical trials. It remains unclear whether the in vivo ligation efficiency will translate to patients and whether the immune response to the click chemistry components could limit repeated dosing.
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Click chemistry reverses tumour drug resistance in vivo
