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Tumor-Associated Macrophages (TAM) represent the major inflammatory component of the stroma of many tumors, able to affect different aspects of the neoplastic tissue. Many observations indicate that TAM express several M2-associated protumoral functions, including promotion of angiogenesis, matrix remodelling and suppression of adaptive immunity. The protumoral role of TAM in cancer is further supported by clinical studies that found a correlation between the high macrophage content of tumors and poor patient prognosis and by evidence showing that long-term use of non-steroidal anti-inflammatory drugs reduces the risk of several cancers. Here, we discuss evidence supporting the view that TAM represent a unique and distinct M2-skewed myeloid population and a potential target of anti-cancer therapy.

Cells of the monocyte-macrophage lineage play a central role in the orchestration and resolution of inflammation. Plasticity is a hallmark of mononuclear phagocytes, and in response to environmental signals these cells undergo different forms of polarized activation, the extremes of which are called classic or M1 and alternative or M2. NF-B is a key regulator of inflammation and resolution, and its activation is subject to multiple levels of regulation, including inhibitory, which finely tune macrophage functions. Here we identify the p50 subunit of NF-B as a key regulator of M2-driven inflammatory reactions in vitro and in vivo. p50 NF-B inhibits NF-B-driven, M1-polarizing, IFN-␤ production. Accordingly, p50-deficient mice show exacerbated M1-driven inflammation and defective capacity to mount allergy and helminth-driven M2-polarized inflammatory reactions. Thus, NF-B p50 is a key component in the orchestration of M2-driven inflammatory reactions.

Macrophages are cells of the innate immunity constituting the mononuclear phagocyte system and endowed with remarkable different roles essential for defense mechanisms, development of tissues, and homeostasis. They derive from hematopoietic precursors and since the early steps of fetal life populate peripheral tissues, a process continuing throughout adult life. Although present essentially in every organ/tissue, macrophages are more abundant in the gastro-intestinal tract, liver, spleen, upper airways, and brain. They have phagocytic and bactericidal activity and produce inflammatory cytokines that are important to drive adaptive immune responses. Macrophage functions are settled in response to microenvironmental signals, which drive the acquisition of polarized programs, whose extremes are simplified in the M1 and M2 dichotomy. Functional skewing of monocyte/macrophage polarization occurs in physiological conditions (e.g., ontogenesis and pregnancy), as well as in pathology (allergic and chronic inflammation, tissue repair, infection, and cancer) and is now considered a key determinant of disease development and/or regression. Here, we will review evidence supporting a dynamic skewing of macrophage functions in disease, which may provide a basis for macrophage-centered therapeutic strategies.