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

Abstract 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.