Macrophage receptor with collagenous structure (MARCO) is a protein that in humans is encoded by the MARCO gene. MARCO is a class A scavenger receptor that is found on particular subsets of macrophages. Scavenger receptors are pattern recognition receptors (PRRs) found most commonly on immune cells. Their defining feature is that they bind to polyanions and modified forms of a type of cholesterol called low-density lipoprotein (LDL). MARCO is able to bind and phagocytose these ligands and pathogen-associated molecular patterns (PAMPs), leading to the clearance of pathogens and cell signaling events that lead to inflammation. As part of the innate immune system, MARCO clears, or scavenges, pathogens, which leads to inflammatory responses. The scavenger receptor cysteine-rich (SRCR) domain at the end of the extracellular side of MARCO binds ligands to activate the subsequent immune responses. MARCO expression on macrophages has been associated with tumor development and also with Alzheimer's disease, via decreased responses of cells when ligands bind to MARCO. Structure MARCO is a transmembrane protein that has 5 domains (see figure). The domain within the cell is called the cytoplasmic domain, as well as a transmembrane domain. The extracellular regions of MARCO include a spacer domain, a collagenous domain, and the SRCR domain. The SRCR domain is required for MARCO binding to ligands, via 2 highly conserved arginine residues, termed the RxR motif. Other members of the class A scavenger receptors tend to have alpha helical coiled coil domains, but MARCO does not. The C-terminal SRCR domain of MARCO affects the ability of the receptor to bind and take up ligand, activate inflammatory signaling, and adhere to surfaces. Cell expression MARCO is expressed on a subset of tissue-resident macrophages in normal tissues, as well as circulating monocytes, dendritic cells, and B cells. MARCO is typically present on the macrophages in the marginal zone of the spleen and the medullary lymph nodes, but it is also found in the liver. Dendritic cells increase expression of MARCO when exposed to certain pathogens, resulting in alterations to the cytoskeleton of dendritic cells and increased phagocytosis. MARCO is highly expressed by macrophages and monocytes in the tumor microenvironment (TME), including tumor-associated macrophages (TAMs) and monocytic myeloid-derived suppressor cells (mMDSCs). Expression of MARCO correlated (FDR < 0.01 and R > 0.2126212) with expression of genes associated with immunosuppressive TAMs, such as CD68, CD163, MSR1, IL4R, CHIA, TGFB1, IL10, and IL37, whereas no correlation was