The tumor microenvironment maintains a sufficient immunosuppressive state owing to the existence of the immunosuppressive factors. The most prominent such factor is transforming growth factor β (TGF-β), which is mainly provided by platelets. Moreover, platelets have been shown to be the main accomplice in assisting tumor metastasis. Therefore, blocking tumor-associated platelets is endowed with functions of enhancing immunity and reducing metastasis. Herein, we designed a tumor microenvironment-responsive nitric oxide (NO) release nanoparticle, Ptx@AlbSNO, which was able to specifically and safely co-deliver the antiplatelet agent NO and the chemotherapeutic agent paclitaxel (Ptx) into tumor tissues and inhibit platelet−tumor cell interactions. We discovered that Ptx@AlbSNO could successfully block tumor-specific platelet functions, thereby suppressing the process of tumor epithelial−mesenchymal transition (EMT), preventing platelet adhesion around circulating tumor cells (CTCs) and reducing distant metastasis. In vivo studies demonstrate that the co-delivery of NO and Ptx can suppress primary tumor growth. With the ability to effectively inhibit activated platelets and TGF-β secretion in tumors, Ptx@AlbSNO can enhance intratumoral immune cell infiltration to reverse the immunosuppressive tumor microenvironment.
Major challenges for cancer treatment are how to effectively eliminate primary tumor and sufficiently induce immunogenic cell death (ICD) to provoke a robust immune response for metastasis control. Here, a self-assembled cascade bioreactor was developed to improve cancer treatment with enhanced tumor penetration and synergistic therapy of starvation, chemodynamic (CDT) and photothermal therapy. Ultrasmall FeS-GOx nanodots were synthesized with glucose oxidase (GOx) as template and induced by paclitaxel (PTX) to form self-assembling FeS-GOx@PTX (FGP)
via
hydrophobic interaction. After accumulated at tumor sites, FGP disassembles to smaller FeS-GOx for enhanced deep tumor penetration. GOx maintains high enzymatic activity to catalyze glucose with assistant of oxygen to generate hydrogen peroxide (H
2
O
2
) as starvation therapy. Fenton reaction involving the regenerated H
2
O
2
in turn produced more hydroxyl radicals for enhanced CDT. Following near-infrared laser at 808 nm, FGPs displayed pronounced tumor inhibition
in vitro
and
in vivo
by the combination therapy. The consequent increased exposure to calreticulin amplified ICD and promoted dendritic cells maturation. In combination with anti-CTLA4 checkpoint blockade, FGP can absolutely eliminate primary tumor and avidly inhibit distant tumors due to the enhanced intratumoral infiltration of cytotoxic T lymphocytes. Our work presents a promising strategy for primary tumor and metastasis inhibition.
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