Available online 22 December 2025
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Short article
Mapping cellular targets of covalent cancer drugs in the entire mammalian body
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https://doi.org/10.1016/j.cell.2025.11.030
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Highlights
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Copper saturation and repeated reactions enabled 3D whole-body click labeling
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vCATCH enabled unbiased and registered drug-binding profiling in the mouse brain
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vCATCH revealed cellular binding of covalent cancer drugs across the adult mouse body
Summary
As our understanding of biological systems reaches single-cell and high spatial resolutions, it becomes imperative that pharmacological approaches match this precision to understand drug actions. This need is particularly urgent for the targeted covalent inhibitors that are currently re-entering the stage for cancer treatments. By leveraging the unique kinetics of click reactions, we developed volumetric clearing-assisted tissue click chemistry (vCATCH) to enable deep and homogeneous click labeling across the three-dimensional (3D) mammalian body. With simple and passive incubation steps, vCATCH offers cellular-resolution drug imaging in the entire adult mouse. We combined vCATCH with hydrogel-based reinforcement of three-dimensional imaging solvent-cleared organs (HYBRiD) imaging and virtual reality to visualize and quantify in vivo targets of two clinical cancer drugs, afatinib and ibrutinib, which recapitulated their known pharmacological distribution and revealed previously unreported tissue and cell-type engagement potentially linked to off-target effects. vCATCH provides a body-wide, unbiased platform to map covalent drug engagements at unprecedented scale and precision.
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Keywords
drug targetstissue clearingwhole-body imagingtargeted covalent inhibitors
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These authors contributed equally
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© 2025 The Authors. Published by Elsevier Inc.