Magnetic nanoparticles as nanocarriers and immune modulators for cancer targeted therapy

Superparamagnetic iron oxide nanoparticles (SPIONs) and in general magnetic nanoparticles (MNPs) have attracted great interest in the cancer therapy as nanocarriers. SPIONs can be multifunctionalized and manipulated by an external gradient magnetic field (GMF) and an alternating magnetic field (AMF), mediating targeting of different classes of biologically active molecules (chemotherapeutics, antibodies, nucleic acids) and hyperthermia, respectively. SPIONs can also be used not only to target cancer cells, but also the tumor microenvironment (TME), by modulating the activities of the infiltrating host 's cells residing there to restore an anti-tumor response. Indeed, tumor-associated macrophages (TAMs) are the major cell population in the TME and play a prominent role in favoring tumor progression, displaying an M2 phenotype. Macrophages are highly plastic cells, which can acquire different phenotypes according to the microenvironmental stimuli they receive, and can be polarized towards two extreme phenotypes, the classically-activated M1 pro-inflammatory one and the alternatively-activated M2 antiinflammatory and pro-tumor one. TAMs display an irregular unfolded protein response (UPR) in their endoplasmic reticulum (ER) to endure the surrounding environment stress and ensure the protumor activity. Recent studies have suggested that the protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) arm of the UPR is uniquely upregulated in TAMs to contribute to the metabolic adaptation necessary to support tumor growth; while other studies have shown that the arm inositol-Requiring Protein 1 (IRE-1) induces the macrophage polarization towards proinflammatory phenotype (M1) by activating the XBP1 protein. In this contest, the re-education of TAMs from the M2 immunosuppressive to the M1 tumoricidal phenotype by modulating UPR with nanotechnology represents an alternative and effective anti-cancer strategy.