Nonferrous Ferroptosis Inducer Manganese Molybdate Nanoparticles to Enhance Tumor Immunotherapy.

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.