Adaptable peptide-based therapeutics modulating tumor microenvironment for combinatorial radio-immunotherapy

Area of Science:

• Biomedical Engineering
• Cancer Research
• Drug Delivery Systems

Background:

• Radiotherapy is a conventional cancer treatment, but its effectiveness is limited by the immunosuppressive tumor microenvironment.
• Overcoming this immunosuppression is crucial for enhancing abscopal therapeutic efficacy.

Purpose of the Study:

• To develop morphology-adaptable peptide-based therapeutics for combinatorial radio-immunotherapy.
• To simultaneously block immune checkpoints and induce immunogenic cell death (ICD).

Main Methods:

• Co-assembling a pentapeptide with an indoleamine 2,3-dioxygenase 1 (IDO-1) inhibitor (NLG919).
• Creating therapeutics with pH-adaptable morphology (nanofibrils to nanoparticles) and triggered release of NLG919.
• Evaluating in vivo tumor accumulation, retention, and therapeutic efficacy in mice.

Main Results:

• The morphology-adaptable therapeutics showed enhanced tumor accumulation and retention compared to persistent counterparts.
• Combined treatment with therapeutics and gamma-ray radiation boosted tumor immunogenicity.
• IDO-1 inhibition by NLG919 led to tryptophan depletion, reversing the immunosuppressive tumor microenvironment.

Conclusions:

• Morphology-adaptable peptide-based therapeutics can effectively reverse immunosuppression during radiotherapy.
• This approach offers a novel strategy for combinatorial radio-immunotherapy by enhancing ICD and checkpoint blockade.