Combinatorial therapy with resveratrol sensitizes glioblastoma to NKG2D CAR-T cells.

Chimeric antigen receptor T-cell (CAR-T) therapies have shown potential in clinical trials for glioblastoma, yet treatment responses vary due to heterogeneous antigen expression and post-treatment immune escape. NKG2D-based CAR-T cells have exhibited a favorable safety profile in patients with hematologic malignancies and demonstrated potent antitumor activity in xenograft models, including those of glioblastoma. Nevertheless, glioma cells could evade immune recognition by downregulating or proteolytically shedding NKG2D ligands. To enhance the efficacy of NKG2D CAR-T therapy, we investigated its combination with preclinical agents capable of penetrating the blood-brain barrier that could upregulate NKG2D ligands on glioma cells. Our study revealed that resveratrol (RSV), a bioactive polyphenol, significantly increased the surface expression of NKG2D ligands on glioblastoma cells. RSV pretreatment sensitized these cells to NKG2D CAR-T-mediated killing in vitro. Additionally, the combination of RSV with NKG2D CAR-T cells demonstrated potent antitumor activity in vivo. Mechanistically, RSV potentially induced NKG2D ligand expression via activation of the p53 signaling pathway. These preclinical findings identify RSV as a promising pharmacological adjuvant that enhances NKG2D CAR-T efficacy in glioblastoma, supporting further translational and clinical evaluation of this combinatory approach.