Abstract:The treatment of glioblastoma (GBM) faces significant challenges due to the immunosuppressive microenvironment, the blood-brain barrier (BBB), and high heterogeneity, resulting in poor responses to conventional therapies such as immune checkpoint inhibitors (ICIs). Bispecific antibodies (BsAbs), which can simultaneously bridge T cells and tumor antigens (such as EGFRvIII, HER2, B7-H3), have demonstrated potential in overcoming the therapeutic challenges of GBM in preclinical studies. This review systematically analyzes the research progress and mechanisms of action of BsAbs, including bispecific T-cell engagers (BiTEs), in the treatment of GBM. Studies have shown that BsAbs targeting the aforementioned antigens can effectively activate T cells, promote their tumor infiltration, and specifically kill GBM cells, significantly improving survival rates in various preclinical models (such as orthotopic xenograft models and humanized models), with some models showing a significant extension of survival time (P<0.0001). BiTE therapy also shows promise in inducing durable antitumor effects. However, there are still critical bottlenecks to address in the application of BsAbs in GBM, including BBB penetration efficiency, potential off-target toxicity, and immunogenicity. Additionally, this review explores the latest advances in optimizing BsAbs, such as enhancing specificity through affinity and configuration engineering, and combination strategies like co-administration with ICIs, radiotherapy, or nanodelivery systems to improve efficacy and safety. With advancements in antibody engineering technology, optimally designed BsAbs are expected to become effective therapeutic tools for improving the prognosis of GBM patients.