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<p>Utilizing CAR-T cells to eliminate circulating tumor cells (CTCs) and inhibit metastasis is a promising strategy. However, this approach is hindered by the lack of specific antigens. Membrane-bound HSP70 (mHSP70) is commonly expressed on the cell membrane of numerous tumor types, notably on CTCs, making it an ideal target for CAR-T therapy to treat these malignancies and prevent metastasis. Here, we generated CAR T cells based on natural ligand granzyme B (GrB-CAR T) targeting mHSP70. GrB-CAR T cells exhibited potent cytotoxicity against a broad spectrum of cancer cell lines and stem-like cancer cells in vitro and effectively inhibited xenograft tumor growth in vivo. Importantly, CTCs maintain mHSP70 expression in xenograft models, and GrB-CAR T cells markedly decreased the number of CTCs, thereby preventing cancer metastasis. Moreover, despite human granzyme B exhibits cross-reactivity with mouse and macaque mHSP70—particularly given the complete homology between macaque and human mHSP70—no obvious adverse effects were observed in the animals treated with GrB-CAR T cells. These results demonstrate GrB-CAR T cells as a safe and effective approach with broad-spectrum anticancer activity and provide compelling experimental evidence for CAR T cell-mediated metastasis inhibition through targeting CTCs.</p>

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Granzyme B-based CAR-T cells targeting membrane-bound HSP70 suppress solid tumor growth and metastasis

  • 期刊论文

  • 发表日期：

    2026年4月18日

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  • Bin Sun,
  • Jing Guo,
  • Dong Yang,
  • Qiancheng Hu,
  • Haiyan Ma,
  • Panwen Tian,
  • Nan Liu,
  • Longbao Lv,
  • Lanzhen Yan,
  • Hao Ding,
  • Maoyong Fu,
  • Hongfeng Gou,
  • Dan Cao,
  • Dan Liu,
  • Peng Shi,
  • Nianyong Chen,
  • Weimin Li,
  • Xudong Zhao

摘要

Utilizing CAR-T cells to eliminate circulating tumor cells (CTCs) and inhibit metastasis is a promising strategy. However, this approach is hindered by the lack of specific antigens. Membrane-bound HSP70 (mHSP70) is commonly expressed on the cell membrane of numerous tumor types, notably on CTCs, making it an ideal target for CAR-T therapy to treat these malignancies and prevent metastasis. Here, we generated CAR T cells based on natural ligand granzyme B (GrB-CAR T) targeting mHSP70. GrB-CAR T cells exhibited potent cytotoxicity against a broad spectrum of cancer cell lines and stem-like cancer cells in vitro and effectively inhibited xenograft tumor growth in vivo. Importantly, CTCs maintain mHSP70 expression in xenograft models, and GrB-CAR T cells markedly decreased the number of CTCs, thereby preventing cancer metastasis. Moreover, despite human granzyme B exhibits cross-reactivity with mouse and macaque mHSP70—particularly given the complete homology between macaque and human mHSP70—no obvious adverse effects were observed in the animals treated with GrB-CAR T cells. These results demonstrate GrB-CAR T cells as a safe and effective approach with broad-spectrum anticancer activity and provide compelling experimental evidence for CAR T cell-mediated metastasis inhibition through targeting CTCs.