Mild magnetothermal enhanced nanocatalytic immunotherapy for solid tumors by immune cell activation and intratumoral infiltration

Immunotherapy is based on the systemic immunity activation against malignacies, which is becoming one of the most promising modalities in solid tumor therapy. Unfortunately, the outcomes of the present immunotherapy remain unsatisfactory or even disappointing in most types of solid tumors, largely because of the immunosuppressive tumor microenvironment and hardly permeable barriers of solid tumors against immune cell infiltrations. Herein, a novel strategy of concurrently stimulating innate and adaptive immunity while enhancing immune cell infiltration in solid tumor, is proposed using a rationally designed magnetic nanocatlytic medicine (ZnCoFe₂O₄@ZnMnFe₂O₄-PBA, ZCMFP) for mild magnetic hyperthermia therapy (MHT) mediated immune response activations. Briefly, ZCMFP generates reactive oxygen species (ROS) catalyzed by released Fe^2+/3+ ions from the nanomedicine in response to acidic tumor microenvironment (TME), provoking the innate immunity by triggering M1 polarization of tumor-associated macrophages (TAMs). Meanwhile, the co-released Mn²⁺ promotes the maturation of dendritic cells (DCs) via STING pathway for antigen presentation, which awakes T cells and thus activates the adaptive immunity. The mild MHT also regulates heat shock protein (HSP) and reduces vascular endothelial growth factor (VEGF) intratumorally, resulting in the elevated expressions of adhesion molecules (ICAM-1/VCAM-1) by endothelial cells, which facilitates the recruitment and infiltration of effector immune cells. This strategy features robust and durable immune responses leading to the marked inhibitions on the growths both orthotopic and metastasis tumors, providing a possible solution for solid tumor immunotherapy in clinics.