Tumour-specific bioorthogonal synthesis of proteolysis-targeting chimeras and nanoparticles boosts T cell activity

Redirecting immune cells or therapeutic molecules to cancer targets without harming healthy tissues remains a major challenge. Here we present a tumour-selective ligation strategy that enables in situ assembly of proximity-based therapies, including proteolysis-targeting chimeras and nanotechnology-based immunotherapy. The system uses a tumour-enriched amino acid mimic to uncage a chemical tag, triggering a rapid and selective bond-forming reaction with a matching tag on a therapeutic module. This decaging-to-ligation chemistry allows precise recruitment of proteins or immune cells at the tumour site. In mouse models, proteolysis-targeting chimeras were synthesized locally at concentrations sufficient for degradation activity, while immune cell-engaging nanoparticles formed only in treated tumours, leading to a 14.8-fold increase in T cell activation. The approach induced strong tumour regression with minimal systemic toxicity. Unlike uncontrolled therapies, which caused marked increases in white blood cell counts, the controlled ligation system showed negligible side effects. This strategy offers a generalizable method for activating therapeutic assemblies in vivo, overcoming key limitations of proximity-mediated cancer treatments.