CXCR4 induces memory formation over exhaustion in CAR-T cells to achieve durable leukemia targeting
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.
Authors
- Yukihide Momozawa (ORCID: https://orcid.org/0000-0001-5638-3504)
- Naoyuki Uchida (ORCID: https://orcid.org/0000-0002-4123-6154)
- Yuho Najima
- Mari Hashimoto
- Hiroshi Kajita
- Ryo Nakagawa (ORCID: https://orcid.org/0000-0001-5367-6731)
- Yoriko Saito
- Kazushige Katsura (ORCID: https://orcid.org/0000-0002-4333-0224)
- Jonathan Moody
- Takehiro Fukami
- Chen Bibi
- Shinsuke Takagi
- Mariko Tomizawa-Murasawa
- Keiyo Takubo (ORCID: https://orcid.org/0000-0002-1736-7592)
- L. D. Shultz
- Emi Kanamaru
- Makoto Iwasaki (ORCID: https://orcid.org/0000-0002-7564-157X)
- Saera Fujiki
- Saumya Agrawal
- Mikako Shirouzu
- Yasuyuki Negishi (ORCID: https://orcid.org/0000-0003-4974-1574)
- Kazuharu Hanada (ORCID: https://orcid.org/0000-0002-5998-1849)
- Minggao Liang
- Masahiko Katô
- Fumihiko Ishikawa
- Nahoko Suzuki
- Michiho Shindo
- Akiko Kaneko
- Jay W. Shin
- Shuichi Taniguchi
- Chung Chau Hon
- Miki Kojima
- Hanae Amitani-Iijima
- Yuriko Sorimachi
- Maiko Kobayashi
- Ari Itoh-Nakadai
- Kaori Sato
Institutions
- Tokyo Institute of Technology (JP)
- Agency for Science, Technology and Research (SG)
- National University of Singapore (SG)
- Japan Advanced Institute of Science and Technology (JP)
- Tohoku University (JP)
- Tokyo Metropolitan Komagome Hospital (JP)
- National Center for Global Health and Medicine (JP)
- Hamanomachi Hospital (JP)
- Jackson Laboratory (US)
- Human Technopole (IT)
- RIKEN Center for Integrative Medical Sciences (JP)
- Toranomon Hospital (JP)
- Nippon Medical School (JP)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-01-26
- DOI
- https://doi.org/10.1038/s41467-025-67745-x
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- RIKEN