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

• 成果类型: Article
• 署名作者: Chiu, David Kung-Chun; Zhang, Xiangyue; Cheng, Bowie Yik-Ling; Liu, Qiang; Hayashi, Kazukuni; Yu, Bo; Lee, Ryan; Zhang, Catherine; An, Xiuli; Rajadas, Jayakumar; Reticker-Flynn, Nathan E.; Rankin, Erinn B.; Engleman, Edgar G.
• 署名单位: Stanford University; Stanford University; Stanford University; New York Blood Center; Stanford University; Stanford University; Stanford University; Stanford Cancer Institute
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8287
• DOI: 10.1126/science.adr3026
• 发表日期: 2025-04-25
• 关键词: macrophages; cells; expression; liver; receptor; tolerance; subsets; injury; set

摘要

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.