To assess SEB‐induced T cell cytotoxicity through tumor‐targeted engager design, we engineered a tumor‐targeted superantigen by fusing the SEB variants with an anti‐mesothelin nanobody[42] Cytolytic studies demonstrated that T cells activated by the SEB variants #22 and #30 displayed stronger T cell cytotoxicity against cancer cells as compared to SEB #1. This evidence concerns the gene SETBP1 and cancer.