Nanomaterials have been identified as a potential therapeutic option for targeting myeloid-derived suppressor cells (MDSCs), which are known to play a crucial role in tumor metastasis and treatment resistance. Here, we report a unique immunologically active nanomaterial composed of ferumoxytol and poly(I : C) (FP-NPs) and investigate its immunoregulatory activities on MDSCs in metastatic melanoma. In vivo assays demonstrated that FP-NPs had the ability to significantly impede the progression of metastatic melanoma and decrease the MDSC population in the lungs, spleen, and bone marrow of mice. Both in vivo and in vitro experiments revealed that FP-NPs reduced the number of granulocytic MDSCs and promoted the differentiation of monocytic MDSCs into anti-tumor M1 macrophages. Transcriptome sequencing indicated that FP-NPs significantly altered the expression of several genes involved in immunity. Analysis of Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and quantitative real-time PCR revealed that FP-NPs significantly increased the expression of the myeloid cell differentiation-related gene interferon regulatory factor 7 and activated interferon beta-related signaling pathways, which stimulated the differentiation of MDSCs into M1 macrophages. These findings suggest that FP-NPs, a unique nanomaterial with immunological properties, can induce MDSCs to differentiate into M1 macrophages, potentially offering new treatment prospects for metastatic melanoma in the future.