Sugar-based drug-free systemic immunoregulating and imageable nanoparticles promote the efficacy of immune checkpoint inhibitors in aggressive cancer

Abstract Poor drug delivery and an unresponsive tumor microenvironment (TME) hinder the treatment of glioblastoma (GBM) and pancreatic cancer (PC). Targeting macrophage polarization through nanoparticle (NP) internalization represents a promising approach to regulate the TME and enhance immunotherapy. Here, we introduce a galactose -based NP designed for monocarboxylate transporter 4 (MCT-4)-mediated transport in cells, promoting M2-to-M1 macrophage polarization and disrupting tumor cell mitochondrial function to trigger apoptosis. The CG-based NP promotes M1 macrophage accumulation, facilitates the M2-to-M1 transition, and exhibits the potential to overcome the obstacles in GBM and PC treatment. This approach enhances immune checkpoint inhibitor efficacy while overcoming the challenging TME. Additionally, incorporating Fe 3 O 4 promotes ferroptosis and enables the use of these NPs in magnetic resonance imaging-based monitoring. Diverging from previous studies that focused on synthesizing nanomaterials, our work has pioneered a synthetic methodology that generates immune-stimulating NPs through a precursor-only hydrothermal reaction and galactose surface engineering. This approach can be meticulously tailored for precise immunotherapeutic applications, which is beneficial for targeting the intricacies of challenging cancers.