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Improving T-cell engager efficacy in glioblastoma with multi-antigen targeting and novel delivery approaches
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DOI：10.1007/s00401-026-03063-w.png)
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Abstract
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Glioblastoma remains a challenging disease to approach with immunotherapy due to pronounced antigen heterogeneity, immunosuppressive tumor microenvironment, and barriers to effective molecule delivery within the central nervous system. T-cell engagers provide an off-the-shelf approach to redirect endogenous T cells toward tumor cells. However, bispecific formats are constrained by intra- and interpatient antigen heterogeneity, which can limit therapeutic efficacy. In this review, we examine trispecific T-cell engagers (TriTEs) as an emerging strategy to address this limitation by simultaneously targeting multiple tumor-associated antigens. We discuss principles guiding antigen selection in glioblastoma, summarize available preclinical evidence supporting multispecific engagement, and outline key design considerations, including molecular architecture, stability, half-life extension, and safety optimization. We further review delivery strategies, such as gene-encoded expression, cellular carriers, and blood–brain barrier modulation, that may improve tumor access and the durability of TriTEs. Together, these considerations position TriTEs as a modular immunotherapy platform relevant to glioblastoma and other heterogeneous solid tumors.
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