Mitogen-Activated Protein Kinase Pathway: A Critical Regulator in Tumor-associated Macrophage Polarization

The notion that inflammation is a critical component of cancer has been researched extensively. Tumor-associated macrophages (TAMs) are among the inflammatory cells that greatly influence cancer. In the tumor microenvironment (TME), macrophages can either stimulate or inhibit tumorigenesis. TAMs that stimulate tumor cell proliferation (M2-phenotype) enrich the TME with growth factors and immunosuppressive molecules, whereas tumor inhibitory TAMs (M1-phenotype) initiate the immune response to dampen tumor progression. Shifting between phenotypes is controlled by several components of the TME. Targeting macrophages, specifically inhibiting M2 TAMs, has been introduced successfully in cancer immunotherapy. However, signaling mechanisms underlining TAM polarization are largely unknown. This review analyzed studies of the role of mitogen-activated protein kinase (MAPK) as a determinant of macrophage polarization. It is proposed that activation of MAPK, particularly extracellular signal-regulated kinase 1/2 and p38, might favor the differentiation into M2 TAMs. Thus, pharmacological modification of MAPK pathways will potentially offer exciting new targets in cancer immunotherapy.