A Biomimetic Metal-Organic Framework Nanosystem Modulates Immunosuppressive Tumor Microenvironment Metabolism to Amplify Immunotherapy

Abstract

In the immunosuppressive tumor microenvironment (iTME), lactate secretion by cancer cells facilitates cell escape via M1 to M2 macrophage polarization, and T cell exhaustion. Therefore, lactate is a promising tumor immunotherapy target. In this study, we constructed a biomimetic nanosystem to modulate iTME metabolism to amplify immunogenic cell death (ICD)-induced immunotherapy. Metal-organic frameworks were coated with platelet membranes (PM) for tumor site-specific delivery and rationally designed to carry lactate oxidase (Lox) which catalytically consumed lactate, while oxaliplatin (Oxa) induced ICD. Due to PM-mediated targeting, the biomimetic nanosystem selectively accumulated in tumors and inhibited tumor growth. Encouragingly, due to effective iTME modulation, enhanced cytotoxic T cell infiltration in tumors was observed. Also, tumor-associated macrophage (TAM) phenotypes were polarized from M2 to M1 types, and regulatory T cell (Treg) levels decreased in vivo. Increased CD8⁺ T to CD4⁺ T cell ratios in peripheral blood and spleen were also observed. Thus, our biomimetic nanosystem effectively modulated the iTME and inhibited tumor growth by consuming lactate and amplifying ICD-induced immunotherapy. We provide new avenues into cancer immunotherapy, with a specific emphasis on iTME modulation, which lays the foundation for translational biomimetic nanosystems in clinical settings.

Keywords: Biomimetic nanosystem; Immunosuppressive tumor microenvironment; Lactate; Lactate oxidase; Oxaliplatin.