While most nanomaterials are designed to assist tumor therapy, some inorganic nanoparticles have been reported to impede cancer development. We assume that the immune response elicited by these foreign nanoparticles might be associated with the remodeling of immune landscape in the tumor microenvironment (TME). We studied representative inorganic nanoparticles widely used in the biomedical field and first demonstrated that needle-shaped hydroxyapatite (n-nHA), granule-shaped hydroxyapatite, and silicon dioxide can effectively impair tumor progression in vivo. Substantial multinucleated giant cells (MNGCs) were formed around these antitumor nanoparticles, while the ratio of monocytes and macrophages was decreased in the TME. We found that high expression of the STXBP6 protein induced by n-nHA-treated macrophages triggers autophagy, which markedly promotes macrophage fusion into MNGCs. In this way, extensive depletion of tumor-associated macrophages in the TME was achieved, which suppressed tumor growth and metastasis. This intrinsic antitumor immunity of inorganic nanoparticles should not be neglected when designing future nanomedicines to treat cancer.