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TitleCXCR4 induces memory formation over exhaustion in CAR-T cells to achieve durable leukemia targeting.
Journal, issue, pagesNat Commun, Vol. 17, Issue 1, Page 101, Year 2026
Publish dateJan 26, 2026
AuthorsAri 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 / Yoriko Saito / Michiel de Hoon / Jay W Shin / Fumihiko Ishikawa /
PubMed AbstractChimeric 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 ...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.
External linksNat Commun / PubMed:41587986 / PubMed Central
MethodsEM (single particle)
Resolution2.97 Å
Structure data

62427

9kmc

EMDB-62427, PDB-9kmc:
Cryo-EM structure of the heterotrimeric interleukin-2 receptor in complex with interleukin-2 and anti-CD25 Fab S417
Method: EM (single particle) / Resolution: 2.97 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

Source
  • homo sapiens (human)
  • sythetic construct (others)
  • synthetic construct (others)
KeywordsIMMUNE SYSTEM / CYTOKINE

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