Manganese Ferrite Nanoparticles Enhance the Sensitivity of Hepa1-6 Hepatocellular Carcinoma to Radiation by Remodeling Tumor Microenvironments

Int J Mol Sci. 2021 Mar 5;22(5):2637. doi: 10.3390/ijms22052637.


We evaluated the effect of manganese ferrite nanoparticles (MFN) on radiosensitization and immunologic responses using the murine hepatoma cell line Hepa1-6 and the syngeneic mouse model. The clonogenic survival of Hepa1-6 cells was increased by hypoxia, while being restricted by ionizing radiation (IR) and/or MFN. Although MFN suppressed HIF-1α under hypoxia, the combination of IR and MFN enhanced apoptosis and DNA damage in Hepa1-6 cells. In the Hepa1-6 syngeneic mouse model, the combination of IR and MFN notably limited the tumor growth compared to the single treatment with IR or MFN, and also triggered more frequent apoptosis in tumor tissues than that observed under other conditions. Increased expression of PD-L1 after IR was not observed with MFN alone or the combination of IR and MFN in vitro and in vivo, and the percentage of tumor-infiltrating T cells and cytotoxic T cells increased with MFN, regardless of IR, in the Hepa1-6 syngeneic mouse model, while IR alone led to T cell depletion. MFN might have the potential to overcome radioresistance by alleviating hypoxia and strengthening antitumor immunity in the tumor microenvironment.

Keywords: nanoparticles; radiosensitization; radiotherapy; tumor hypoxia; tumor microenvironment.

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / immunology
  • Carcinoma, Hepatocellular / pathology
  • Carcinoma, Hepatocellular / radiotherapy*
  • Cell Line, Tumor
  • Ferric Compounds / chemistry
  • Ferric Compounds / pharmacology*
  • Liver Neoplasms / immunology
  • Liver Neoplasms / pathology
  • Liver Neoplasms / radiotherapy*
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / pathology
  • Manganese Compounds / chemistry
  • Manganese Compounds / pharmacology*
  • Mice
  • Nanoparticles / chemistry
  • Nanoparticles / therapeutic use*
  • Radiation, Ionizing*
  • Radiation-Sensitizing Agents / chemistry
  • Radiation-Sensitizing Agents / pharmacology*
  • T-Lymphocytes / immunology
  • T-Lymphocytes / pathology
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / immunology
  • Tumor Microenvironment / radiation effects*


  • Ferric Compounds
  • Manganese Compounds
  • Radiation-Sensitizing Agents
  • manganese ferrite