Targeting Immunoglobulin Superfamily Member 9 (IGSF9) to Overcome Acute Myeloid Leukemia Resistance to CAR-T Therapy

Background: Chimeric antigen receptor (CAR)-T cell therapy faces substantial barriers in acute myeloid leukemia (AML), yet the mechanisms by which AML evades CAR-T cell cytotoxicity—through tumor-intrinsic factors and microenvironmental suppression—remain poorly defined. Immunoglobulin superfamily member 9 (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.