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The immunosuppressive nature of the tumor microenvironment poses a significant challenge to effective immunotherapies against glioblastoma (GB). Boosting the immune response is critical for successful therapy. Here, we adopted a cancer gene therapy approach to induce T‐cell‐mediated killing of the tumor through increased activation of the immune system. Patient‐based three‐dimensional (3D) GB models were infected with a replication‐deficient adenovirus (AdV) armed with the class II major histocompatibility complex (MHC‐II) transactivator (CIITA) gene (Ad‐CIITA). Successful induction of surface MHC‐II was achieved in infected GB cell lines and primary human GB organoids. Infection with an AdV carrying a mutant form of CIITA with a single amino acid substitution resulted in cytoplasmic accumulation of CIITA without subsequent MHC‐II expression. Co‐culture of infected tumor cells with either peripheral blood mononuclear cells (PBMCs) or isolated T‐cells led to dramatic breakdown of GB organoids. Intriguingly, both wild‐type and mutant Ad‐CIITA, but not unarmed AdV, triggered immune‐mediated tumor cell death in the co‐culture system, suggesting an at least partially MHC‐II‐independent process. We further show that the observed cancer cell killing requires the presence of either CD8+ or CD4+ T‐cells and direct contact between GB and immune cells. We did not, however, detect evidence of activation of canonical T‐cell‐mediated cell death pathways. Although the precise mechanism remains to be determined, these findings highlight the potential of AdV‐mediated CIITA delivery to enhance T‐cell‐mediated immunity against GB. [ABSTRACT FROM AUTHOR]