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

Abstract

Antibody-mediated blockade of the PD-1/PD-L1 immune checkpoint has revolutionized cancer treatment. However, their efficacy is often limited by the compensatory upregulation of PD-L1 synthesis, which sustains surface expression upon blockade. FOXM1, a pivotal oncogenic transcription factor overexpressed in diverse cancers, directly transactivates PD-L1 expression, presenting a strategic upstream therapeutic target. To concurrently suppress both membrane-bound and newly synthesized intracellular PD-L1, we modularly designed a dual-functional nanoassembly via the co-assembly of a fluorinated FOXM1-inhibitory peptide and a PD-L1-targeting aptamer. This nanoassembly leverages fluorination to enhance nanoassembly stability and cytosolic delivery efficiency to achieve a programmable two-stage PD-L1 suppression. The aptamer module mediates tumor-targeted binding and blocks surface PD-L1, after which the internalized nanoassembly releases the peptide module to transcriptionally suppress PD-L1 via FOXM1 inhibition. Consequently, this nanoassembly achieves potent PD-L1 downregulation, addressing the limitations of conventional antibody blockade that primarily targets surface proteins. In murine models, this dual-inhibition strategy robustly reinvigorates antitumor immunity, significantly suppressing tumor growth and metastasis. Our work establishes a dual-functional nanoassembly that programmably controls PD-L1 expression, presenting a promising approach to circumvent adaptive resistance in cancer immunotherapy by durably targeting the source of PD-L1 expression.