Biomimetic Iron-Based Nanoparticles Remodel Immunosuppressive Tumor Microenvironment for Metabolic Immunotherapy

Introduction: Immunotherapy has led to a paradigm shift in reinvigorating treatment of cancer. Nevertheless, tumor associated macrophages (TAMs) experience functional polarization on account of the generation of suppressive metabolites, contributing to impaired antitumor immune responses.
Methods: Hence, metabolic reprogramming of tumor microenvironment (TME) can synergistically improve the efficacy of anti-tumor immunotherapy. Herein, we engineered an iron-based nanoplatform termed _ERFe₃O₄ NPs. This platform features hollow Fe₃O₄ nanoparticles loaded with the natural product emodin, the outer layer is coated with red blood cell membrane (mRBCs) inserted with DSPE-PEG2000-galactose. This effectively modulates lactate production, thereby reversing the tumor immune suppressive microenvironment (TIME).
Results: The _ERFe₃O₄ NPs actively targeted TAMs on account of their ability to bind to M2-like TAMs with high expression of galectin (Mgl). _ERFe₃O₄ NPs achieved efficient ability to reverse TIME via the production of reducing lactate and prompting enrichment iron of high concentrations. Furthermore, _ERFe₃O₄ NPs resulted in heightened expression of CD16/32 and enhanced TNF-α release, indicating promotion of M1 TAMs polarization. In vitro and in vivo experiments revealed that _ERFe₃O₄ NPs induced significant apoptosis of tumor cells and antitumor immune response.
Discussion: This study combines Traditional Chinese Medicine (TCM) with nanomaterials to synergistically reprogram TAMs and reverse TIME, opening up new ideas for improving anti-tumor immunotherapy.

Keywords: metabolic immunotherapy, nanoparticles, reprograming, iron oxide, macrophages