Combined mild magnetic hyperthermia and calcium ion regulation for enhanced immunotherapy of orthotopic liver cancer

Abstract

Cancer immunotherapy relies on immune cells activation to fight malignancies. Liver serves as the important organs with abundant immune cells. However, in the process of liver tumor development, immune cells lose original function of fighting tumors affected by tumor immunosuppressive microenvironment. Here, a hyaluronic acid-modified calcium phosphate-coated magnetic nanoparticles (named as MSCH) is used to remodel immunosuppressive microenvironment of liver tumors to multiple activate immune cells based on mild magnetic hyperthermia therapy (MHT) and calcium ions regulation strategy. In detail, intra-tumoral acidic microenvironment and mild MHT effectively promote calcium ions release from MSCH to activate casepase-1, resulting in tumor-associated macrophages (TAMs) M1 polarization. Meanwhile, mild MHT significantly upregulate RAE-1ɛ proteins expression in liver cancer cells, ligands for natural killer group 2 member D (NKG2D), resulting in natural killer (NK) cell activation. Moreover, the synergistic effect of mild MHT and calcium overload in cancer cells enables tumor immunogenic cell death (ICD) to activate robust adaptive immune responses. Most importantly, the mild MHT featuring excellent deep tissue penetration ensures the heat accumulation in liver tumors. The multi-activated immune cells therapy strategy based on mild MHT and calcium ions regulation has demonstrated excellent therapeutic effects for orthotopic liver cancer tumor.