Nonferrous Ferroptosis Inducer Manganese Molybdate Nanoparticles to Enhance Tumor Immunotherapy

Abstract Tumor immunotherapy is an important tool in oncology treatment. However, only a small percentage of patients have an effective immune response to tumor immunotherapy due to the poor infiltration of pro‐inflammatory immune cells in immune “cold” tumors and an immunosuppressive network in the tumor microenvironment (TME). Ferroptosis has been widely used as a novel strategy to enhance tumor immunotherapy. Herein, manganese molybdate nanoparticles (MnMoOx NPs) depleted the highly expressed glutathione (GSH) in tumors and inhibited glutathione peroxidase 4 (GPX4) expression, thus triggering ferroptosis, inducing immune cell death (ICD), further releasing damage‐associated molecular patterns (DAMPs), and enhancing tumor immunotherapy. Furthermore, MnMoOx NPs can efficiently suppress tumors, promote the maturation of dendritic cells (DCs), infiltrate T cells, and reverse the immunosuppressive microenvironment, making the tumor an immune “hot” tumor. Combination with an immune checkpoint inhibitor (ICI) (α‐PD‐L1) further enhanced the anti‐tumor effect and inhibited metastases as well. The work provides a new idea for the development of nonferrous inducers of ferroptosis to enhance cancer immunotherapy.