4.8 Article

A hierarchical tumor-targeting strategy for eliciting potent antitumor immunity against triple negative breast cancer

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BIOMATERIALS
卷 296, 期 -, 页码 -

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ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2023.122067

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Hierarchical targeting; Triple negative breast cancer; Immune checkpoint blockade; Stimulator of interferon gene pathway; Tumor-infiltrating antigen-presenting cells

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This study develops a hierarchical targeting strategy to prepare a core-shell-structural nanodrug that can block programmed death ligand 1 (PD-L1) and deliver a stimulator of interferon gene (STING) agonist to tumor-infiltrating antigen-presenting cells (APCs). The nanodrug efficiently accumulates in tumor sites and stimulates APCs maturation to prime anti-tumor immunity, sensitizing triple negative breast cancer (TNBC) to immune checkpoint blockade therapy.
Triple negative breast cancer (TNBC) as a highly aggressive and metastatic malignancy lacks targeting therapies nowadays. Moreover, although immune checkpoint blockade (ICB) is known to trigger anti-tumor immune response, most TNBC falls into the immunologically cold category unsuitable for ICB therapy due to insufficient lymphocyte infiltration. Herein, we develop a hierarchical targeting strategy for preparing a core-shell-structural nanodrug to concurrently block the programmed death ligand 1 (PD-L1) and deliver a stimulator of interferon gene (STING) agonist into tumor-infiltrating antigen-presenting cells (APCs). The nanodrug complexed the interferon stimulatory DNA (ISD) for STING activation in its core, conjugated PD-L1 antibody (aPD-L1) on its shell through a matrix metalloproteinase-2 (MMP-2) substrate peptide, and incorporated hidden mannose in its sublayer. Through aPD-L1-mediated active targeting of tumor cells and tumor-infiltrating APCs, the nanodrug efficiently accumulated in tumor sites. Then, the PD-L1-conjugating peptide was cleaved by tumor-enriched MMP-2, leaving aPD-L1 on target cells for ICB while exposing mannose to mediate targeted delivery of ISD into tumor-infiltrating dendritic cells (DCs) and tumor-associated macrophages (TAMs). Activating the STING signaling in DCs and TAMs not only stimulated the APCs maturation to prime anti-tumor immunity but also induced their chemokine secretion to promote tumor infiltration of anti-tumor effector T cells, thus sensitizing TNBC to the ICB therapy. Consequently, a potent antitumor immunity was evoked to effectively inhibit the tumor growth and metastasis in mice bearing orthotopic 4T1 breast cancer, showing the great potential in treating immunologically cold tumors.

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