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Tumour-specific bioorthogonal synthesis of proteolysis-targeting chimeras and nanoparticles boosts T cell activity
Chunhong Wang1, Mengqi Chen1, Mingzhe Zhang1
1Beijing National Laboratory for Molecular Sciences, Radiochemistry and Radiation Chemistry Key Laboratory of Fundamental Science, College of Chemistry and Molecular Engineering, Peking University, Beijing, China.
Abstract:
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.
Insights
This study introduces a novel tumour-selective ligation strategy for in situ assembly of cancer therapies. This approach precisely targets cancer cells, enhancing therapeutic efficacy while minimizing systemic toxicity and side effects.
Area of Science:
- Oncology
- Chemical Biology
- Immunotherapy
Background:
- Targeting cancer therapies to tumour sites without affecting healthy tissues is a significant challenge.
- Current proximity-based therapies face limitations in precise in vivo assembly and control.
Purpose of the Study:
- To develop a tumour-selective ligation strategy for in situ assembly of proximity-based cancer therapies.
- To enable precise recruitment of therapeutic molecules and immune cells at the tumour site.
- To overcome limitations in current cancer treatment strategies.
Main Methods:
- Utilized a tumour-enriched amino acid mimic to uncage a chemical tag.
- Developed a rapid and selective bond-forming reaction between tagged components.
- Applied the strategy for in situ synthesis of proteolysis-targeting chimeras and immunotherapy nanoparticles in mouse models.
Main Results:
- Achieved local synthesis of proteolysis-targeting chimeras at effective concentrations.
- Demonstrated in situ formation of immune cell-engaging nanoparticles exclusively in treated tumours.
- Observed a 14.8-fold increase in T cell activation and significant tumour regression.
- Showed minimal systemic toxicity and negligible side effects compared to uncontrolled therapies.
Conclusions:
- The tumour-selective ligation strategy enables precise in vivo assembly of proximity-based cancer therapies.
- This approach enhances therapeutic efficacy and reduces systemic toxicity.
- The generalizable method offers a promising solution for advanced cancer treatment.
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