The Use of Iron Oxide Nanoparticles to Reprogram Macrophage Responses and the Immunological Tumor Microenvironment

Abstract

The synthesis and functionalization of iron oxide nanoparticles (IONPs) is versatile, which has enhanced the interest in studying them as theranostic agents over recent years. As IONPs begin to be used for different biomedical applications, it is important to know how they affect the immune system and its different cell types, especially their interaction with the macrophages that are involved in their clearance. How immune cells respond to therapeutic interventions can condition the systemic and local tissue response, and hence, the final therapeutic outcome. Thus, it is fundamental to understand the effects that IONPs have on the immune response, especially in cancer immunotherapy. The biological effects of IONPs may be the result of intrinsic features of their iron oxide core, inducing reactive oxygen species (ROS) and modulating intracellular redox and iron metabolism. Alternatively, their effects are driven by the nanoparticle coating, for example, through cell membrane receptor engagement. Indeed, exploiting these properties of IONPs could lead to the development of innovative therapies. In this review, after a presentation of the elements that make up the tumor immunological microenvironment, we will review and discuss what is currently known about the immunomodulatory mechanisms triggered by IONPs, mainly focusing on macrophage polarization and reprogramming. Consequently, we will discuss the implications of these findings in the context of plausible therapeutic scenarios for cancer immunotherapy.

Dealing with Macrophage Plasticity to Address Therapeutic Challenges in Head and Neck Cancers

“…Thus, macrophages have emerged as a promising therapeutic target in the field of new cancer treatments due to their strategic involvement in the TME. Because of their great plasticity, macrophages can be reprogrammed according to specific signals in order to pass from a pro-tumor phenotype to an anti-tumor one, and then to oppose cancer progression [ 29 , 60 , 70 ]. Therefore, we aimed to confirm the macrophages plasticity with our polarization model and found an upregulation of M1 markers in M2 treated macrophages.…”

Impact of Superparamagnetic Iron Oxide Nanoparticles on THP-1 Monocytes and Monocyte-Derived Macrophages

“…These findings may point to dramatic side effects relating to the involvement of iron-activated M1 macrophages in endothelial damage and the formation of atherosclerotic plaques ( Zhu et al, 2011 ; Laskar et al, 2013 ). In contrast, the immunomodulatory mechanism of SPIONs triggers the macrophage polarization in tumor tissue towards a M1-like anti-tumor phenotype ( Reichel et al, 2019 ; Mulens-Arias et al, 2021 ). These phenomenon is a promising approach for tumor therapy and has been approved in cell culture and murine models ( Poller et al, 2017 ; Zhang et al, 2020 ).…”

From Microenvironment Remediation to Novel Anti-Cancer Strategy: The Emergence of Zero Valent Iron Nanoparticles

“…It has been reported that high ROS levels induced by iron overload can polarize macrophages to the M1 subtype through p53 acetylation [110]. Furthermore, a similar reprogram macrophage response was notified with iron oxide NPs treatment [32]. Since the acidity of the interstitium has resulted from their high metabolic activity and overexpression of V-ATPase, the pH in the TME is spatially and temporally heterogeneous compared to normal tissues.…”

“…ROS was recently described as an important signal transduction mediator in various cellular functions and cell types. Iron oxides NPs were recently reported to modulate tumor immunity through reprograming their differentiation and affecting anti-cancer phenotypes [32]. Nevertheless, the multiple roles of ZVI NPs in the modulation of both cancer cell death and stemness -as well as angiogenesis and immune response in the tumor microenvironment (TME)have not been comprehensively reviewed or discussed.…”