Monocarboxylate transporter blockage-enabled lactate redistribution reshapes immunosuppressive tumor microenvironment and enhances chemodynamic immunotherapy

Abstract

The immunosuppressive tumor microenvironment (TME) hinders T cells infiltration and prevents a sufficient immune response. Monocarboxylate transporter (MCT)-mediated lactate accumulation not only leads to tumor acidification but also recruits immunosuppressive cells, which greatly limits the therapeutic efficacy of immunotherapy. In this work, we report an MCT blockage strategy using a manganese-based metal organic framework (MnMOF) for enhanced chemodynamic immunotherapy. Syrosingopine (Syr) was found to prevent tumor cells from excreting lactate into the extracellular environment via MCT, thus lowering the intracellular pH and increasing the intracellular H2O2 levels. Afterward, the Mn ion-triggered Fenton-like reaction was amplified by the increased H2O2 levels and strongly acidic conditions in tumor cells. The dying tumor cells induced by chemodynamic therapy released damage-associated molecular patterns, promoting the activation and proliferation of T cells. Furthermore, Syr reduced the lactate levels of the extracellular TME to restore immune activity, including the M1 polarization of tumor-associated macrophages, the activation of dendritic cells and cytotoxic T lymphocytes, and a reduction in immunosuppressive cells. Overall, this Syr@PEG-MnMOF74 nanocomplex enhanced chemodynamic immunotherapy and effectively inhibited the invasion and metastasis of CT26 tumors.