MARCO (macrophage receptor with collagenous structure) is a pattern recognition receptor (PRR) expressed on macrophages that binds Gram-positive and Gram-negative bacteria and unopsonized particles 1. MARCO also binds secretoglobin SCGB3A2 and functions in receptor-mediated endocytosis and phagocytosis. In tumor microenvironments, MARCO serves as a marker of pro-tumor macrophage subpopulations. MARCO+ tumor-associated macrophages (TAMs) characterize immune-resistant, macrophage-enriched infiltration patterns associated with worse patient prognosis across multiple cancer types. In glioblastomas, MARCO expression marks a mesenchymal pro-tumor macrophage subpopulation almost exclusively found in IDH1-wild-type tumors and correlates with worse prognosis 2. Similarly, in intrahepatic cholangiocarcinoma, MARCO+ TAMs co-localize with cathepsin E+ tumor cells in protumorigenic areas characterized by elevated epithelial-mesenchymal transition, angiogenesis, and suppressed immune responses, with co-infiltration predicting poorest survival 3. Therapeutically, anti-MARCO antibodies targeting these immunosuppressive TAMs decrease tumor vascularization, alter macrophage metabolism, and activate natural killer cell killing, synergizing with checkpoint immunotherapy 4. Additionally, tumor-specific MARCO splicing variants in triple-negative breast cancer promote progression through HIF-1α stabilization and metabolic dysregulation 5, representing novel therapeutic targets.