*4.2. SPIONs and Immunomodulation of the Monocyte-Macrophage Axis* 4.2.1. Solid Tumors and TME

Cancers could be divided into two main types, solid and liquid tumors. Both of them are characterized by uncontrolled cell growth. Whereas liquid tumors, also known as blood cancers, can affect blood cells and their precursors [133], solid tumors can occur in many parts of the body and they can be separated into two major groups according to where they originate: carcinoma (epithelial tissue) and sarcoma (connective tissue) [134]. However, in compliance with Global Cancer Statistics 2020, solid tumors alone account for approximately 90% of adult human cancers [1]. Solid tumors are not only composed of cancer cells. Immune cells, such as B and T lymphocytes or macrophages, as well as non-immune cells, including endothelial and stroma cells, are part of a highly complex ecosystem, which directly interacts with cancer cells, called the TME [135]. The TME is also composed of several non-cellular effectors, such as cytokines, chemokines, and the extracellular matrix (ECM) [136]. Moreover, two key hallmarks of the TME include hypoxia, resulting from anarchic neo-angiogenesis and promoting tumor aggressiveness, and immunosuppression, whereby cancer cells manage to escape from immune cells [137,138].

Immunosuppressive effects observed in the TME are sustained by a group of cells, called immunosuppressive cells, such as regulatory T cells, regulatory B cells, MDSCs, and TAMs [139]. TAMs have an important role in cancer progression as they can account for up to 50% of some solid tumors [140]. The vast majority of TAMs exhibit an immunosuppressive and pro-tumoral M2-like phenotype [141]. However, TAMs can also display an M1-like phenotype that could be correlated with tumor regression [142].
