Erythropoietin in Tumor Immunity: Mechanistic Evidence, Clinical Cautions, and Translational Opportunities

Abstract

Simple Summary Erythropoietin (EPO) is best known as the hormone that stimulates red blood cell production and is used to treat selected forms of anemia. Cancer-related EPO biology is broader and more context-dependent. Recent studies show that tumor-derived EPO can reprogram macrophages and dendritic cells, while stress erythropoiesis can expand immunosuppressive CD71-positive nucleated erythroid cells. By contrast, evidence for direct EPO signaling in malignant cells remains inconsistent because receptor abundance is low, detection methods vary, and receptor transcripts do not necessarily indicate functional cell-surface signaling. This review differs from earlier reviews focused on tumor cells and angiogenesis by organizing the evidence according to the source of EPO, the responding cellular compartment, and the strength of causal evidence. It also separates practical screening methods from definitive functional validation. Clinically, erythropoiesis-stimulating agents remain supportive care agents with established restrictions; they are not anticancer therapies. The main translational opportunity is to identify tumor-localized, immunosuppressive EPO signaling that might be interrupted without compromising erythropoiesis or vascular safety.