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Background Glioblastoma is the most aggressive tumor type of the central nervous system, with a prognosis of 14-16 months. Human TERT (h-TERT) is expressed in glioblastoma in about 80% of types intracellularly. Among solid tumors, mutations exist in the telomerase reverse transcriptase promoter, making tumor cells proliferate for longer than normal cells with extended telomers and self-renewal capacity. Although expressed intracellularly, h-TERT, can be expressed on the surface of cells through MHC class 1 expression (HLA*02:01). Natural killer (NK) cells are part of the innate immune system that respond to tumors as a first-line defense. Memory Like NK cells have been shown to have enhanced interferon-γ production and cytotoxicity against leukemia, and we hypothesize they will have a similar response in solid tumors such as glioblastoma. NK cells are known to kill cells that downregulate MHC class 1. NK cells are also known to work with cells of the adaptive immune system, such as T cells.Methods Human-derived NK cells were differentiated and primed into memory-like NK cells through high-dose IL-12, IL-15, and IL-18 cytokines and then engineered to express a CAR targeting HLA-A02 expression of hTERT, and cocultured with human glioblastoma lines.Results Coculture showed increased interferon-γ in CAR-Memory like NK cells compared to conventional NK cells. CAR-Memory-like NK cells also show tumor growth control and increase cytotoxicity in glioblastoma cell lines and brain tumor-initiating lines derived from patients. Finally CAR-Memory-like NK cells show tumor control in an NSG xenograft model.Conclusions Memory-like NK Cells targeting HLA-A02:hTERT successfully show a potential to target glioblastoma. Through cell co-culture experiment Memory-like NK Cells demonstrate an increase in interferon-γ and cytotoxicity.