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.