Tumor-derived erythropoietin acts as an immunosuppressive switch in cancer immunity

Science. 2025 Apr 25;388(6745):eadr3026. doi: 10.1126/science.adr3026. Epub 2025 Apr 25.

Abstract

Successful cancer immunotherapy requires a patient to mount an effective immune response against tumors; however, many cancers evade the body's immune system. To investigate the basis for treatment failure, we examined spontaneous mouse models of hepatocellular carcinoma (HCC) with either an inflamed T cell-rich or a noninflamed T cell-deprived tumor microenvironment (TME). Our studies reveal that erythropoietin (EPO) secreted by tumor cells determines tumor immunotype. Tumor-derived EPO autonomously generates a noninflamed TME by interacting with its cognate receptor EPOR on tumor-associated macrophages (TAMs). EPO signaling prompts TAMs to become immunoregulatory through NRF2-mediated heme depletion. Removing either tumor-derived EPO or EPOR on TAMs leads to an inflamed TME and tumor regression independent of genotype, owing to augmented antitumor T cell immunity. Thus, the EPO/EPOR axis functions as an immunosuppressive switch for antitumor immunity.

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular* / immunology
  • Carcinoma, Hepatocellular* / therapy
  • Cell Line, Tumor
  • Erythropoietin* / genetics
  • Erythropoietin* / immunology
  • Erythropoietin* / metabolism
  • Heme / metabolism
  • Humans
  • Immune Tolerance
  • Liver Neoplasms* / immunology
  • Liver Neoplasms* / therapy
  • Mice
  • Mice, Inbred C57BL
  • NF-E2-Related Factor 2 / metabolism
  • Receptors, Erythropoietin* / genetics
  • Receptors, Erythropoietin* / metabolism
  • Signal Transduction
  • T-Lymphocytes / immunology
  • Tumor Escape*
  • Tumor Microenvironment* / immunology
  • Tumor-Associated Macrophages* / immunology
  • Tumor-Associated Macrophages* / metabolism

Substances

  • Erythropoietin
  • Heme
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Receptors, Erythropoietin
  • EPO protein, human