Unlocking Glioblastoma Secrets: Natural Killer Cell Therapy against Cancer Stem Cells

Abstract

Glioblastoma (GBM) represents a paramount challenge as the most formidable primary brain tumor characterized by its rapid growth, aggressive invasiveness, and remarkable heterogeneity, collectively impeding effective therapeutic interventions. The cancer stem cells within GBM, GBM stem cells (GSCs), hold pivotal significance in fueling tumor advancement, therapeutic refractoriness, and relapse. Given their unique attributes encompassing self-renewal, multipotent differentiation potential, and intricate interplay with the tumor microenvironment, targeting GSCs emerges as a critical strategy for innovative GBM treatments. Natural killer (NK) cells, innate immune effectors recognized for their capacity to selectively detect and eliminate malignancies without the need for prior sensitization, offer substantial therapeutic potential. Harnessing the inherent capabilities of NK cells can not only directly engage tumor cells but also augment broader immune responses. Encouraging outcomes from clinical investigations underscore NK cells as a potentially effective modality for cancer therapy. Consequently, NK cell-based approaches hold promise for effectively targeting GSCs, thereby presenting an avenue to enhance treatment outcomes for GBM patients. This review outlines GBM's intricate landscape, therapeutic challenges, GSC-related dynamics, and elucidates the potential of NK cell as an immunotherapeutic strategy directed towards GSCs.

Keywords: GBM; GSCs; NK cells; immunotherapeutic strategy.

Figure 1

Glioblastoma microenvironment. The tumor cells, including GSCs and DGCs (differentiated glioblastoma cells), interact with various types of cells in the tumor microenvironment. GSCs exhibit the capacity for self-renewal, proliferation, and differentiation into diverse cell types within the glioblastoma microenvironment.

Figure 2

The activating receptors and inhibitory receptors related to NK cells regulatory signaling. The NK cell activating receptors include NKG2D, NKp30, NKp44, NKp46, etc. (left), and the receptors of inhibitory receptors include CTLA-4, TIGIT, PD-1, TIM-3, etc. (right).

Figure 3

A “one-two punch” strategy to target GSCs and glioblastoma recurrence. Conventional therapies for glioblastoma, such as chemotherapy and radiotherapy, can eliminate most of the DGCs in the tumor mass. However, GSCs may survive and undergo self-renewal, leading to tumor relapse. The “one-two punch” strategy aims to block the GSC self-renewal and simultaneously activate NK cells to eliminate GSCs and glioblastoma.