For a long time, erythropoietin (EPO) has been regarded as a "blood-boosting miracle" – it stimulates red blood cell production and is an important drug for treating anemia. However, this seemingly mild "blood-boosting factor" actually plays the role of a "mole" in cancer, helping tumors evade the immune system's attacks.
In April 2025, a study from Stanford University titled "Tumor-derived erythropoietin acts as an immunosuppressive switch in cancer immunity" was published in the journal Science. The study found that malignant tumors such as liver cancer actively secrete erythropoietin (EPO). In the tumor microenvironment, EPO's function shifts from promoting hematopoiesis to suppressing immune system function, helping tumors evade immune surveillance.
Figure 1. Article title, journal, and author information
The research team first constructed various gene-edited mouse models of hepatocellular carcinoma (HCC) to clearly distinguish two types of tumor microenvironments:
- Inflammatory "hot" tumors: significantly enriched with CD8⁺ T cells and sensitive to PD-1 inhibitors;
- Non-inflammatory "cold" tumors: scarce in T cells, exhibiting immune evasion and unresponsive to immune checkpoint inhibitor therapy.
Moreover, in mice without signs of anemia, plasma erythropoietin (EPO) levels were still significantly elevated, indicating that EPO is not a compensatory effect but may be a key factor in tumor immune suppression.
Figure 2. EPO/EPOR signaling in macrophages imposes a non-inflammatory tumor immune phenotype
Further analysis revealed that EPO primarily targets intrahepatic Kupffer cells and tumor-associated macrophages (TAMs), activating downstream signals through the erythropoietin receptor (EPOR): downregulation of MHC II expression; significant increase in marker immune regulatory factors such as CD206 and VSIG4; and enhanced infiltration of regulatory T cells (Treg). Human HCC samples also confirmed that EPOR is mainly localized on CD68⁺ immune regulatory macrophages and is associated with tumor progression.
The researchers validated the critical role of the EPO/EPOR signaling axis in tumor immune suppression through various methods. First, in the Trp53-deficient liver cancer model, knocking out the EPO gene in tumor cells significantly reduced tumor size and increased CD8⁺ T cells; next, in LysM-Cre; Epor^fl/fl mice, specifically deleting EPOR on macrophages led to spontaneous tumor regression in some mice; finally, whether through EPOR-targeted siRNA drugs or Tamoxifen-induced EPOR knockout, both significantly enhanced the effect of PD-1 immunotherapy. The study ultimately found that blocking the EPO or EPOR signal can transform "cold" tumors into "hot" tumors, with a large infiltration of TNFα⁺ CD8⁺ memory T cells, and when used in combination with PD-1 antibodies, can even achieve complete tumor clearance.
Molecular mechanism studies showed that after EPO/EPOR activation: NRF2 nuclear translocation is upregulated, initiating antioxidant responses; inducing the expression of heme degradation and iron recycling genes such as HMOX1 and FTH1; inhibiting the transcription of pro-inflammatory factors like IL-1β and CXCL10. Subsequently, the researchers found that knocking out NRF2 eliminated EPO's immune suppressive function in the TME, and tumors were recognized and cleared by CD8⁺ T cells, further supporting the central role of NRF2 in this process.
EPO (erythropoietin) not only plays a crucial role in the hematopoietic system but also its new role in tumor immune regulation is attracting increasing attention. In-depth research on the EPO/EPOR pathway relies on high-quality experimental materials. abinScience provides a variety of products including EPO/EPOR-related proteins and antibodies to support tumor immunology research and mechanism exploration.
