Abstract
Background: Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor in adults, characterized by an immunosuppressive microenvironment. To address the immune desert in GBM, immunocytokine, an innovative recombinant fusion protein that combines antibodies and cytokines, has been proposed. This molecule, targeting tumor cells while stimulating immune cells, effectively enhances the anti-tumor response. Developing a novel immunocytokine presents a promising strategy for GBM. Methods: In this study, we developed a novel immunocytokine, αBC-IL15, composed of a bispecific T cell engager (BsTCE) fused to the interleukin-15 receptor alpha-sushi domain/interleukin-15 complex (IL-15/IL-15Rα). To analyze its affection on immune cells, we co-cultured it with peripheral blood mononuclear cells in vitro. To investigate whether it enhances the cytotoxicity of T cells compared to B7-H3 BsTCE, we performed cytotoxicity assays on cell lines and spheroids in vitro. Moreover, we assessed its efficacy in vivo and analyzed the tumor microenvironment using flow cytometry and bulk sequencing. Results: Our study assessed the bioactivity and efficiency of αBC-IL15. In vitro, αBC-IL15 effectively bound to tumor cells and T cells, inducing immune cell activation, cytokine release, and cytotoxicity toward tumor cells. In vivo, αBC-IL15 connects cytotoxic immune cells with tumor cells, leading to effective immune cell infiltration and potent redirected lysis. Conclusions: Overall, we developed a novel bispecific immunocytokine, αBC-IL15, which targets tumor cells while enriching and activating effector immune cells. This agent significantly enhanced anti-tumor effects both in vitro and in vivo, highlighting its potential to overcome the immunosuppressive microenvironment in GBM. Graphical : Supplementary Information: The online version contains supplementary material available at 10.1186/s12967-025-07321-5.