Iron overload in the tumor microenvironment induces CD8+ T cell ferroptosis and dysfunction PMID: 42173913

ADC Targets in Oncology

2026-04-10

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

Nat Commun. 2026 May 22. doi: 10.1038/s41467-026-73379-4.

Zhenyu Lin ¹ ² , Huanpeng Chen ¹ , Yujing Ke ¹ , Hanyue Xiao ¹ ³ ⁴ , Chao Li ¹ ³ ⁴ , Zilong Wu ¹ ⁵ , Huixin Gao ⁶ , Nanqi Huang ⁷ , Lijuan Lu ⁸ , Peng Sun ⁹ ¹⁰ , Yingjie Bian ¹¹ ¹² ¹³

Affiliations

1. Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou, China.
2. Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
3. State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
4. Guangzhou Medical University, Guangzhou, China.
5. Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
6. Department of Clinical Laboratory, Guangzhou Women and Children Medical Center, Guangzhou Medical University, Guangzhou, China.
7. Department of Gastrointestinal Surgery, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
8. Department of Medical Oncology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
9. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
10. Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China.
11. Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou, China. [email protected].
12. State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. [email protected].
13. Guangzhou Medical University, Guangzhou, China. [email protected].

Abstract

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.