Magnetic-Manipulated NK Cell Proliferation and Activation Enhance Immunotherapy of Orthotopic Liver Cancer

The immunotherapy of deep solid tumorsin the human body, suchas liver cancer, still faces great challenges, especially the inactivationand insufficient infiltration of immune cells in solid tumor microenvironment.Natural killer (NK) cells are gaining ever-increasing attention owingto their unique features and are expected to play an important rolein the liver cancer immunotherapy. However, NK cells are severelyinsufficient and inactivated in solid liver tumor due to the highlyimmunosuppressive intratumor microenvironment, resulting in poor clinicaltherapeutic efficacy. Herein, we propose a mild magnetocaloric regulationapproach using a magnetogenetic nanoplatform MNPs@PEI-FA/pDNA (MPFD),which is synthesized by loading a heat-inducible plasmid DNA (HSP70-IL-2-EGFP)on polyethyleneimine (PEI)- and folic acid (FA)-modified ZnCoFe2O4@ZnMnFe2O4 magnetic nanoparticles(MNPs) to promote the proliferation and activation of tumor-infiltratingNK cells under magnetic manipulation without the limitation of penetrationdepth for orthotopic liver cancer immunotherapy. The magnetothermallyresponsive MPFD serves as a magnetism-heat nanotransducer to inducethe gene transcription of IL-2 cytokine in orthotopic liver tumorfor NK cell proliferation and activation. Both in vitro and in vivo results demonstrate that the remotemild magnetocaloric regulation (similar to 40 degrees C) by MPFD initiatesthe HSP70 promoter to trigger the overexpression of IL-2 cytokinefor subsequent secretion, leading to in situ expansionand activation of tumor-infiltrating NK cells through the IL-2/IL-2receptor (IL-2R) pathways and the resulting prominent tumor inhibition.This work not only evidences the great potential of magnetogeneticnanoplatform but also reveals the underlying proliferation and activationmechanism of NK cells in liver cancer treatment by magnetogeneticnanoplatform.

Automated summary

This study proposes a mild magnetocaloric regulation approach using a magnetogenetic nanoplatform (MPFD) to promote the proliferation and activation of tumor-infiltrating NK cells in liver cancer immunotherapy. The magnetothermally responsive MPFD serves as a magnetism-heat nanotransducer to induce the gene transcription of IL-2 cytokine in orthotopic liver tumor for NK cell proliferation and activation.