Mild Magnetothermal Immunotherapy for Malignant Pleural Effusion.

Abstract

Malignant pleural effusion (MPE) is one of the most difficult complications of cancer to cure, usually indicating poor prognosis in late-stage cancer patients. Due to the presence of a large number of tumor-associated immune cells with the tumor promoting phenotype in MPE and pleural tumors, current clinical therapy offers limited effectiveness. Here, a mild magnetothermal regulation strategy is proposed based on a magnetic nanocatlytic nanoplatform ZCMF@PEG-AF (ZCMF-AF)constructed by surface-modifying anti-F4/80 antibody (AF) on ZnCoFe2O4@ZnMnFe2O4 magnetic nanoparticles (ZCMF) to target and polarize tumor-associated macrophages. Under alternating magnetic field-induced hyperthermia (41-42°C), ZCMF-AF exhibits in situ nanocatalytic production of hydroxyl radicals via released iron ions under acidic cellular environment, which induces repolarization from the immunosuppressed M2 phenotype to the M1 phenotype. More importantly, the tumor cell damage induced by M1 macrophages and magnetic hyperthermia promote the maturation of dendritic cells, which subsequently awakens cytotoxic T lymphocytes to combat tumor cells. The integrated innate and adaptive immunity activations based on ZCMF-AF nano-immunomedicine through intrapleural administration elicit substantially regulated immune microenvironment of MPE and pleural tumors. Moreover, the interpleural magnetic nanoparticle-based immunotherapy effectively reduced the MPE volume and inhibited tumor growth in the pleural cavity, significantly prolonging the survival of the MPE-bearing mice.