CXCR4 induces memory formation over exhaustion in CAR-T cells to achieve durable leukemia targeting.

Authors

• Ari Itoh-Nakadai
• Minggao Liang
• Michiho Shindo
• Chen Bibi
• Mariko Tomizawa-Murasawa
• Saera Fujiki
• Akiko Kaneko
• Emi Kanamaru
• Mari Hashimoto
• Hiroshi Kajita
• Yoshinari Ando
• Miki Kojima
• Jonathan Moody
• Makoto Iwasaki
• Shinsuke Takagi
• Ryo Nakagawa
• Saumya Agrawal
• Hanae Amitani-Iijima
• Kaori Sato
• Yuriko Sorimachi
• Nahoko Suzuki
• Takehiro Fukami
• Kazuharu Hanada
• Satoshi Morita
• Kazushige Katsura
• Takehisa Matsumoto
• Maiko Kobayashi
• Masahiko Kato
• Yasuyuki Negishi
• Mikako Shirouzu
• Yuho Najima
• Keiyo Takubo
• Chung Chau Hon
• Naoyuki Uchida
• Shuichi Taniguchi
• Yukihide Momozawa
• Piero Carninci
• Leonard D. Shultz, The Jackson LaboratoryFollow
• Yoriko Saito
• Michiel de Hoon
• Jay W Shin
• Fumihiko Ishikawa

Document Type

Article

Publication Date

1-26-2026

Original Citation

Itoh-Nakadai A, Liang M, Shindo M, Bibi C, Tomizawa-Murasawa M, Fujiki S, Kaneko A, Kanamaru E, Hashimoto M, Kajita H, Ando Y, Kojima M, Moody J, Iwasaki M, Takagi S, Nakagawa R, Agrawal S, Amitani-Iijima H, Sato K, Sorimachi Y, Suzuki N, Fukami T, Hanada K, Morita S, Katsura K, Matsumoto T, Kobayashi M, Kato M, Negishi Y, Shirouzu M, Najima Y, Takubo K, Hon C, Uchida N, Taniguchi S, Momozawa Y, Carninci P, Shultz LD, Saito Y, de Hoon M, Shin J, Ishikawa F. CXCR4 induces memory formation over exhaustion in CAR-T cells to achieve durable leukemia targeting. Nat Commun. 2026; 17(1):101

Keywords

JMG, Receptors, CXCR4, Humans, Animals, Immunotherapy, Adoptive, Receptors, Chimeric Antigen, Mice, Immunologic Memory, Leukemia, Myeloid, Acute, Xenograft Model Antitumor Assays, Memory T Cells, T-Lymphocytes, Mice, Inbred NOD, Female, Cell Line, Tumor

ISSN

2041-1723

PMID

41587986

DOI

https://doi.org/10.1038/s41467-025-67745-x

Abstract

Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment of B-cell malignancies, but its success in acute myeloid leukemia (AML) remains limited. Durable responses depend on the formation of long-lived memory T cells, whereas T cell exhaustion contributes to non-response and relapse. In patients with AML who achieved remission after cord blood transplantation, we here first observe enrichment of memory T cells with high expression of the chemokine receptor CXCR4. Next, we show that engineering CAR-T cells to co-express CXCR4 enhances their persistence and anti-leukemic activity in patient-derived xenograft models. Using single-cell profiling and metabolic analysis, we find that CXCR4 promotes memory-associated transcriptional programs, reduces exhaustion, and supports oxidative metabolism. These effects are observed with CAR-T cells targeting CD25 or CD96 as AML-associated targets. Our results indicate that CXCR4 strengthens CAR-T cell memory and durability, offering a strategy to improve immunotherapy outcomes in AML and beyond.

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 International License.