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<p>While iron homeostasis in cancer cells is well-established, its role in mediating crosstalk between tumors and CD8<sup>+</sup> T cells within the tumor microenvironment (TME) remains largely elusive. In this study, we compare iron levels across primary tissues populated by CD8<sup>+</sup> T cells. Contrary to the systemic iron deficiency commonly found in cancer patients, the TME exhibits marked iron enrichment compared to lymphatic fluid and peripheral blood, a phenomenon primarily attributed to tumor necrosis. However, this iron-overloaded TME is detrimental to CD8<sup>+</sup> T cells, triggering their ferroptosis and dysfunction. Mechanistically, tumoral T cell receptor (TCR) hyperactivation and tumor-derived hepcidin cooperatively downregulate the iron exporter SLC40A1 in CD8<sup>+</sup> T cells, leading to intracellular iron accumulation and ferroptosis. Both genetic restoration of SLC40A1 and iron chelation inhibit CD8<sup>+</sup> T cell ferroptosis and restore their cytotoxic activity, thereby suppressing tumor growth. Finally, to enhance chimeric antigen receptor T (CAR-T) cell adaptability to the iron-overloaded TME, we engineer SLC40A1-overexpressing CAR-T cells. These engineered cells resist ferroptosis induced by the TME and elicit potent anti-tumor immunity.</p>

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Iron overload in the tumor microenvironment induces CD8+ T cell ferroptosis and dysfunction

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月22日

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  • Zhenyu Lin,
  • Huanpeng Chen,
  • Yujing Ke,
  • Hanyue Xiao,
  • Chao Li,
  • Zilong Wu,
  • Huixin Gao,
  • Nanqi Huang,
  • Lijuan Lu,
  • Peng Sun,
  • Yingjie Bian

摘要

While iron homeostasis in cancer cells is well-established, its role in mediating crosstalk between tumors and CD8+ T cells within the tumor microenvironment (TME) remains largely elusive. In this study, we compare iron levels across primary tissues populated by CD8+ T cells. Contrary to the systemic iron deficiency commonly found in cancer patients, the TME exhibits marked iron enrichment compared to lymphatic fluid and peripheral blood, a phenomenon primarily attributed to tumor necrosis. However, this iron-overloaded TME is detrimental to CD8+ T cells, triggering their ferroptosis and dysfunction. Mechanistically, tumoral T cell receptor (TCR) hyperactivation and tumor-derived hepcidin cooperatively downregulate the iron exporter SLC40A1 in CD8+ T cells, leading to intracellular iron accumulation and ferroptosis. Both genetic restoration of SLC40A1 and iron chelation inhibit CD8+ T cell ferroptosis and restore their cytotoxic activity, thereby suppressing tumor growth. Finally, to enhance chimeric antigen receptor T (CAR-T) cell adaptability to the iron-overloaded TME, we engineer SLC40A1-overexpressing CAR-T cells. These engineered cells resist ferroptosis induced by the TME and elicit potent anti-tumor immunity.