Unlocking the Promise of Antitumor Hyperthermia‐Immunotherapy with Spiky Surface Topology

Abstract Uveal melanoma (UM) is the most prevalent primary intraocular malignant tumor in adults with high mortality rate. Recently, immunotherapy has shown great success in other tumors, however, its therapeutic effect in UM is unsatisfactory, possibly due to the insufficient immune cell infiltration and low immunogenicity of UM. Thus, an efficient therapeutic strategy to reverse the immunosuppressive tumor microenvironment is required. Herein, a PD‐L1 modified hierarchical structure consisting of a magnetic Fe ₃ O ₄ core and spiky silica shell (MNP@Spiky/PD‐L1) is developed to reverse the immunosuppressive tumor microenvironment and trigger powerful antitumor immune responses. The MNP@Spiky can induce enhanced immunogenic cell death as well as physical activation of innate immunity. First, tumor cells are disrupted directly by magnetic hyperthermia effect and released tumor‐associated antigens to initiate anti‐tumor immune responses. Meanwhile, the spiky surface of MNP@Spiky augmented tumor antigen uptake as well as maturation of dendritic cells through inflammasome activation. By further associating with PD‐L1‐targeting antibody, MNP@Spiky/PD‐L1 reversed the immunosuppressive tumor microenvironment and triggered powerful antitumor immune responses. Overall, this synergistic therapeutic strategy effectively reprogramed tumor microenvironment and achieved tumor eradication, which sheds light on clinical UM immunotherapy.