Ferrimagnetic Vortex Nanoring-Mediated Mild Magnetic Hyperthermia Imparts Potent Immunological Effect for Treating Cancer Metastasis

Abstract

Cancer metastasis is a serious concern and a major reason for treatment failure. Herein, we have reported the development of an effective and safe nanotherapeutic strategy that can eradicate primary tumors, inhibit metastasizing to lung, and control the metastasis and growth of distant tumors. Briefly, ferrimagnetic vortex-domain iron oxide nanoring (FVIO)-mediated mild magnetic hyperthermia caused calreticulin (CRT) expression on the 4T1 breast cancer cells. The CRT expression transmitted an "eat-me" signal and promoted phagocytic uptake of cancer cells by the immune system to induce an efficient immunogenic cell death, further leading to the macrophage polarization. This mild thermotherapy promoted 88% increase of CD8 + cytotoxic T lymphocyte infiltration in distant tumors and triggered immunotherapy by effectively sensitizing tumors to the PD-L1 checkpoint blockade. The percentage of CD8 + cytotoxic T lymphocytes can be further increased from 55.4% to 64.5% after combining with PD-L1 blockade. Moreover, the combination treatment also inhibited the immunosuppressive response of the tumor, evidenced by significant down-regulation of myeloid-derived suppressor cells (MDSCs). Our results revealed that the FVIO-mediated mild magnetic hyperthermia can activate the host immune systems and efficiently cooperate with PD-L1 blockade to inhibit the potential metastatic spreading as well as the growth of distant tumors.

Hyperthermia Targeting the Tumor Microenvironment Facilitates Immune Checkpoint Inhibitors

“…Nanoparticle-mediated hyperthermia includes photothermal therapy and magnetic hyperthermia. Studies have found that the combination of ICIs (CTLA-4, PD-L1, IDO) and nanoparticle-mediated hyperthermia can promote antigen capture, enhance ICD effect, inhibit Treg cells' function, promote M1 macrophages' differentiation, recruit several folds of tumor-infiltrating lymphocytes, and achieve lasting memory for the inhibition of tumor growth in primary and distant sites (106)(107)(108)(109)(110)(111)(112)(113)(114). The synergetic role of heat and ICIs is further confirmed by results that enhanced tumor antigen-specific T cell responses and an increased Teff to Treg ratio in distant tumors with a combination of RFA and anti-PD-1 mAb administration (105).…”

Magnetic iron oxide nanomaterials: A key player in cancer nanomedicine

“…Moreover, the therapeutic effect could be further improved by cooperation with programmed death ligand 1 checkpoint blockade (Figure 2F). In vivo experiments on 4T1 xenograft mice demonstrated the superior therapeutic effectiveness of this method, which not only eradicated the primary tumors, but also inhibited the growth of distant tumors and lung metastasis 29 …”

“…(F) Illustration of the action mechanism of FVIO‐mediated mild magnetic hyperthermia‐sensitized immune checkpoint therapy. Reproduced with permission 29 . Copyright 2019, American Chemical Society…”

Recent Progress of Potentiating Immune Checkpoint Blockade with External Stimuli—an Industry Perspective

“…A similar study was conducted by Liu et al, where PEGylated ferrimagnetic vortex nanoring (FVIO) with efficient heat induction due to a vortex‐to‐onion magnetization reversal process that was used for inducing local hyperthermia under AMF ( Figure A). [ 87 ] Successful MHT‐induced tumor cell death was confirmed in 4T1, where early apoptosis (38.42%) and late apoptosis (48.96%) were reported after AMF exposure for 5 min. Furthermore, a calreticulin (CRT) signal that promotes phagocytic uptake of cancer cells by the immune system was upregulated in the FVIO plus AMF group, suggesting FVIO‐mediated hyperthermia induces tumor immunogenic properties.…”