Single atom engineering for radiotherapy-activated immune agonist prodrugs

Area of Science:

• Oncology
• Immunology
• Radiochemistry

Background:

• Immunotherapy shows promise in cancer treatment but faces challenges due to on-target, off-tumour toxicity.
• Developing tumour-selective prodrugs activated in a targeted manner is crucial for minimizing systemic side effects and maximizing anti-tumour activity.

Purpose of the Study:

• To introduce a Single Atom Engineering for Radiotherapy-Activated Prodrug (SAE-RAP) technique.
• To develop radiotherapy-activatable small-molecule immune agonist prodrugs for targeted cancer therapy.

Main Methods:

• Molecular engineering of TLR7/8 agonist R848 by introducing a single oxygen atom as a protective mask.
• Preclinical evaluation in tumour mouse models using radiotherapy to activate the prodrug.

Main Results:

• The engineered prodrug showed a >4000-fold reduction in EC50, significantly mitigating systemic toxicity.
• Radiotherapy successfully removed the oxygen mask, locally rescuing prodrug activity and triggering anti-tumour immunity.
• Inhibition of primary and distal tumour growth was observed in preclinical models.

Conclusions:

• The SAE-RAP technique offers a promising strategy for developing targeted, radiotherapy-activatable immune agonist prodrugs.
• This approach can minimize systemic toxicity and enhance anti-tumour efficacy in cancer immunotherapy.
• SAE-RAP holds potential for next-generation combination cancer therapies.