Harnessing the Power\nof Sugar-Based Nanoparticles:\nA Drug-Free Approach to Enhance Immune Checkpoint Inhibition against\nGlioblastoma and Pancreatic Cancer

Cancer cells have a high demand for sugars and express\ndiverse\ncarbohydrate receptors, offering opportunities to improve delivery\nwith multivalent glycopolymer materials. However, effectively delivering\nglycopolymers to tumors while inhibiting cancer cell activity, altering\ncellular metabolism, and reversing tumor-associated macrophage (TAM)\npolarization to overcome immunosuppression remains a challenging area\nof research due to the lack of reagents capable of simultaneously\nachieving these objectives. Here, the glycopolymer-like condensed\nnanoparticle (∼60 nm) was developed by a one-pot carbonization\nreaction with a single precursor, promoting multivalent interactions\nfor the galactose-related receptors of the M2 macrophage (TAM) and\nthereby regulating the STAT3/NF-κB pathways. The subsequently\ninduced M2-to-M1 transition was increased with the condensed level\nof glycopolymer-like nanoparticles. We found that the activation of\nthe glycopolymer-like condensed galactose (CG) nanoparticles influenced\nmonocarboxylate transporter 4 (MCT-4) function, which caused inhibited\nlactate efflux (similar to inhibitor effects) from cancer cells. Upon\ninternalization via galactose-related endocytosis, CG NPs induced\ncellular reactive oxygen species (ROS), leading to dual functionalities\nof cancer cell death and M2-to-M1 macrophage polarization, thereby\nreducing the tumor’s acidic microenvironment and immunosuppression.\nBlocking the nanoparticle–MCT-4 interaction with antibodies\nreduced their toxicity in glioblastoma (GBM) and affected macrophage\npolarization. In orthotopic GBM and pancreatic cancer models, the\nnanoparticles remodeled the tumor microenvironment from “cold”\nto “hot”, enhancing the efficacy of anti-PD-L1/anti-PD-1\ntherapy by promoting macrophage polarization and activating cytotoxic\nT lymphocytes (CTLs) and dendritic cells (DCs). These findings suggest\nthat glycopolymer-like nanoparticles hold promise as a galactose-elicited\nadjuvant for precise immunotherapy, particularly in targeting hard-to-treat\ncancers.