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Related Experiment Video

Updated: Jun 12, 2026

Revealing the Ferroptotic Phenotype of Medulloblastoma

Revealing the Ferroptotic Phenotype of Medulloblastoma

Published on: March 15, 2024

Iron-mediated ferroptosis impairs CAR-T cell function and antitumor efficacy.

Delin Kong^1,2,3,4, Tingting Yang^1,2,3,4, Mengyu Zhao^5,6

¹Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

|June 10, 2026

Summary

Chimeric antigen receptor (CAR)-T cell therapy shows promise, but CAR-T cell dysfunction limits its durability. This study reveals that iron-driven ferroptosis impairs CAR-T cell function, offering a new therapeutic target to enhance cancer treatment efficacy.

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Last Updated: Jun 12, 2026

Revealing the Ferroptotic Phenotype of Medulloblastoma

Revealing the Ferroptotic Phenotype of Medulloblastoma

Published on: March 15, 2024

Generation and Functional Verification of Hypoxia-Sensitive Chimeric Antigen Receptor-T Cells

Generation and Functional Verification of Hypoxia-Sensitive Chimeric Antigen Receptor-T Cells

Published on: June 14, 2024

Area of Science:

Immunology
Oncology
Cell Biology

Background:

Long-term persistence of chimeric antigen receptor (CAR)-T cells is crucial for sustained therapeutic effects in cancer treatment.
Mechanisms underlying CAR-T cell dysfunction, which limit durable efficacy, are not fully understood.

Purpose of the Study:

To investigate the mechanisms of CAR-T cell dysfunction following infusion in patients with hematological malignancies.
To identify novel targets for improving CAR-T cell persistence and antitumor activity.

Main Methods:

Integrated analysis of clinical samples from patients with multiple myeloma and acute lymphoblastic leukemia treated with CAR-T cells.
Preclinical studies using cancer models in female mice and ex vivo cell culture systems.
Investigation of the role of intracellular iron and ferroptosis in CAR-T cell function, including genetic ablation of ACSL4.

Main Results:

CAR-T cell therapy is followed by a 'diminution' phase characterized by ferroptosis and increased serum iron levels.
Excess intracellular iron impairs CAR-T cell function by promoting ferroptosis via mitochondrial reactive oxygen species and lipid peroxidation, partly mediated by ACSL4.
Genetic ablation of ACSL4 in CAR-T cells significantly enhanced antitumor efficacy in preclinical models.

Conclusions:

Iron-driven ferroptosis is a key factor contributing to CAR-T cell dysfunction.
Targeting ferroptosis, specifically by modulating ACSL4, represents a promising strategy to overcome a barrier to durable CAR-T cell therapy and improve clinical outcomes.