A Fluorinated Dual-Functional Nanoassembly Induces Potent Antitumor Immunity via Programmable PD-L1 Suppression

Area of Science:

• Oncology
• Immunology
• Nanotechnology
• Molecular Biology

Background:

• Antibody blockade of PD-1/PD-L1 checkpoints transformed cancer therapy.
• Compensatory PD-L1 upregulation limits antibody efficacy by maintaining surface expression.
• FOXM1, an oncogenic transcription factor, drives PD-L1 expression, representing an upstream therapeutic target.

Purpose of the Study:

• To design a dual-functional nanoassembly for simultaneous intracellular and membrane-bound PD-L1 suppression.
• To overcome adaptive resistance in cancer immunotherapy by targeting PD-L1 synthesis.
• To develop a programmable two-stage PD-L1 suppression strategy.

Main Methods:

• Co-assembly of a fluorinated FOXM1-inhibitory peptide and a PD-L1-targeting aptamer into a nanoassembly.
• Utilizing fluorination for enhanced nanoassembly stability and cytosolic delivery.
• Employing aptamer for tumor targeting and surface PD-L1 blockade, followed by peptide-mediated FOXM1 inhibition.

Main Results:

• Achieved potent, programmable PD-L1 downregulation by targeting both synthesis and surface expression.
• Demonstrated robust inhibition of tumor growth and metastasis in murine models.
• Successfully reinvigorated antitumor immunity through dual-inhibition strategy.

Conclusions:

• The dual-functional nanoassembly effectively circumvents adaptive resistance to PD-1/PD-L1 blockade.
• This approach offers a promising strategy for durable cancer immunotherapy by targeting PD-L1 expression at its source.
• The nanoassembly presents a novel therapeutic modality for managing cancers with adaptive resistance mechanisms.