Glutathione-responsive nanoplatform for intra/extracellular lactate exhaustion to enhance antitumor immunotherapy

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.