Malignant melanoma, one of the most aggressive types of cancer easily metastasizes, making it extremely difficult to treat and unresponsive to current therapies. Recent breakthroughs in nanomaterials-based cancer immunotherapy have provided potential specific strategy for tumor and metastasis inhibition. With the development of nanotechnology, inorganic nanomaterials have been increasingly studied for their potential cancer therapeutic and molecular imaging functions. However, only iron-based nanomaterials have been approved by the Food and Drug Administration (FDA) in inorganic nanomedicines. For promising clinical application, a new type of nanocomposite is engineered by combining ultra-small iron oxide nanoparticles (Fe₃O₄ NPs) and ovalbumin (OVA), denoted as Fe₃O₄-OVA nanocomposites in this study. Interestingly, this is the first time that Fe₃O₄ NPs are found as nano-immunopotentiators helping nanocomposites efficiently stimulate dendritic cell-based immunotherapy and potentially-activate macrophages. These nanocomposites efficiently stimulate the maturation level of bone marrow derived dendritic cell (BMDCs) and corresponding activation of T cells and also potentially-activate macrophages. With the help of the Fe₃O₄ nano-immunopotentiators (Fe₃O₄ NPs), this therapeutic and prophylactic Fe₃O₄-OVA vaccine can not only efficiently inhibit the subcutaneous and metastatic B16-OVA tumor growth but also successfully prevent the formation of subcutaneous and metastatic tumor, providing a promising strategy for expanding the clinical use of Fe-based nanomaterials.