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Background <p>CAR-T cell therapy faces substantial barriers in AML, yet the mechanisms by which AML evades CAR-T cell cytotoxicity—through tumor-intrinsic factors and microenvironmental suppression—remain poorly defined. IGSF9 has recently been identified as an immunosuppressive molecule selectively expressed on AML blasts, but its role in mediating resistance to CAR-T therapy is unknown.</p> Methods <p>We examined IGSF9 expression in AML cells upon CAR-T challenge and conducted in vitro and in vivo assays to define its functional impact on CAR-T cell activity. To overcome IGSF9-mediated suppression, we evaluated two therapeutic strategies: antibody-mediated IGSF9 blockade and the generation of IGSF9-specific CAR-T cells (IG9BBz).</p> Results <p>CAR-T–induced cytotoxic pressure upregulated IGSF9 on AML cells. IGSF9-positive AML cells exhibited resistance to CAR-T killing and impaired CAR-T persistence both in vitro and in vivo. Antibody blockade of IGSF9 restored CAR-T function in xenograft models. Moreover, IG9BBz CAR-T cells demonstrated potent and selective elimination of IGSF9-positive AML cells in both settings.</p> Conclusions <p>Our findings identify a cytokine-driven IGSF9 resistance circuit that suppresses CAR-T cell function in AML. Therapeutic disruption of this pathway through IGSF9 blockade or IGSF9-specific CAR-T cells restores antitumor immunity and provides complementary strategies to overcome CAR-T resistance in AML.</p>

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Targeting immunoglobulin superfamily member 9 (IGSF9) to overcome acute myeloid leukemia resistance to CAR-T therapy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月19日

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  • Xianhui Meng,
  • Fangmin Li,
  • Hong Yu,
  • Chunling Li,
  • Yuxiao Sun,
  • Hongying Wang,
  • Guantong Liu,
  • Jiashen Zhang,
  • Lijun Hui,
  • Fang Li,
  • Shuping Wei,
  • Yaopeng Wang,
  • Zunling Li

摘要

Background

CAR-T cell therapy faces substantial barriers in AML, yet the mechanisms by which AML evades CAR-T cell cytotoxicity—through tumor-intrinsic factors and microenvironmental suppression—remain poorly defined. IGSF9 has recently been identified as an immunosuppressive molecule selectively expressed on AML blasts, but its role in mediating resistance to CAR-T therapy is unknown.

Methods

We examined IGSF9 expression in AML cells upon CAR-T challenge and conducted in vitro and in vivo assays to define its functional impact on CAR-T cell activity. To overcome IGSF9-mediated suppression, we evaluated two therapeutic strategies: antibody-mediated IGSF9 blockade and the generation of IGSF9-specific CAR-T cells (IG9BBz).

Results

CAR-T–induced cytotoxic pressure upregulated IGSF9 on AML cells. IGSF9-positive AML cells exhibited resistance to CAR-T killing and impaired CAR-T persistence both in vitro and in vivo. Antibody blockade of IGSF9 restored CAR-T function in xenograft models. Moreover, IG9BBz CAR-T cells demonstrated potent and selective elimination of IGSF9-positive AML cells in both settings.

Conclusions

Our findings identify a cytokine-driven IGSF9 resistance circuit that suppresses CAR-T cell function in AML. Therapeutic disruption of this pathway through IGSF9 blockade or IGSF9-specific CAR-T cells restores antitumor immunity and provides complementary strategies to overcome CAR-T resistance in AML.