Ultrasound-triggered and Glycosylation Inhibition-enhanced Tumor Piezocatalytic Immunotherapy

Abstract Nanocatalytic immunotherapy holds excellent potential for future cancer therapy due to its rapid activation of the immune system to attack tumor cells. However, a high level of N-glycosylation can protect tumor cells, compromising the anticancer immunity of nanocatalytic immunotherapy. Herein, a reactive oxygen species (ROS)-sensitive scaffold (DBG), comprised of the synergistic components of piezocatalytic bismuth ferrite (BiFeO3) nanosheets and glucose/mannose analog 2-deoxy-d-glucose (2-DG), is designed and engineered for enhanced cancer piezocatalytic immunotherapy. After the implantation in the tumor, DBG generates both ROS and piezoelectric signals when excited with ultrasound irradiation, significantly promoting the activation of cytotoxic T lymphocytes and M1 polarization of tumor-associated macrophages. More importantly, DBG-mediated ROS generation can trigger the release of 2-DG to disrupt the N-glycans synthesis, further overcoming the immunosuppressive microenvironment of tumors. Based on four mouse cancer models, we demonstrated the synergy effects of ultrasound-triggered piezo effects and glycosylation inhibition with an enhanced tumor piezocatalytic immunotherapy. A "hot" tumor-immunity niche was produced to inhibit tumor progress and lung metastasis and elicit strong immune memory effects. This work provides a promising piezocatalytic immunotherapy for malignant solid tumors featuring both low immunogenicity and high levels of N-glycosylation.