| Popis: |
Despite the critical breakthrough achieved by immune checkpoint blockade (ICB) therapies in the clinic, the antitumor effect is seriously restricted by the immunosuppressive tumor microenvironment (ITM). A variety of strategies to alleviate the ITM have been investigated. Direct regulation of lactate metabolism in the tumor microenvironment (TME) holds promise for ITM modulation. Herein, we fabricated a glutathione-responsive PEGylated hollow mesoporous organosilicon (HMOP), with monocarboxylate transporter 1/4 inhibitor (diclofenac, DC) and lactate oxidase (LOX) loaded in/onto the HMOP (denoted as DC-HMOP-LOX). DC-HMOP-LOX could spontaneously be biodegraded in the TME due to the disulfide bonds, and then DC/LOX could be released to exhaust intra/extracellular lactate. DC-HMOP-LOX hindered the transmission of lactate effectively and oxidized lactate directly. Therefore, DC-HMOP-LOX collaboratively depleted lactate in the TME, which induced an immunocompetent TME by activating immune-promoting cells (dendritic cell, T cells, natural killer cells, and M1-macrophage), inactivating immunosuppressive cells (M2-macrophage and bone marrow-derived suppressor cells), and regulating the levels of immune cytokines (IFN-γ, TNF-α, IL-10, and IL-12). The immunocompetent TME ultimately strengthened the antitumor effect of anti-PD1-based immunotherapy. |
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