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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月26日

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  • 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,
  • Yoriko Saito,
  • Michiel de Hoon,
  • Jay W. Shin,
  • Fumihiko Ishikawa

摘要

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.