Click chemistry reverses tumour drug resistance in vivo

July 15, 2026 at 05:00 AM1 min

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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.