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Chimeric 4/9ICR Reprograms Immunosuppressive IL-4 Signals to Enhance B7-H3-Targeted CAR-T Cell Efficacy Against Triple-Negative Breast Cancer

ABSTRACT: Although chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable success in hematologic malignancies, its efficacy against solid tumors remains limited due to the immunosuppressive tumor microenvironment (TME). In triple-negative breast cancer (TNBC), interleukin-4 (IL-4) is markedly enriched and serves as a pivotal regulator driving CAR-T cell exhaustion and resistance to immune checkpoint inhibition. To overcome IL-4-mediated immunosuppression, we engineered an inverted cytokine receptor (4/9ICR), in which the extracellular domain of IL-4 receptor α (IL-4Rα) was fused to the transmembrane and intracellular domains of IL-9Rα. When co-expressed with a B7-H3-targeted CAR, 4/9ICR enables T cells to sequester suppressive IL-4 and convert IL-4 signals into IL-9-like activation, leading to robust phosphorylation of STAT1, STAT3, STAT4, and STAT5. In vitro, both murine and human CAR-4/9ICR-T cells exposed to IL-4 exhibited increased effector cytokine production and enhanced expression of stemness markers. Importantly, CAR-4/9ICR-T cells exerted enhanced tumor control, maintained cytotoxicity, and reduced exhaustion compared with conventional CAR-T cells in vivo. Moreover, 4/9ICR reprogrammed the TME by repolarizing tumor-associated macrophages from an immunosuppressive M2-like to a proinflammatory M1-like phenotype. These findings demonstrate that IL-4/IL-9 signal reprogramming may serve as a clinically applicable strategy to enhance CAR-T efficacy in TNBC and other IL-4-enriched solid tumors.

ORGANISM(S): Mus musculus

PROVIDER: GSE335686 | GEO | 2026/09/08

REPOSITORIES: GEO

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