Study on the anti-tumor effect of PDL1-CAR-γδT cells constructed with nanobody sequences on glioblastoma.

Glioblastoma (GBM) is a highly malignant primary brain tumor, accounting for 50% of gliomas, with limited therapeutic targets and an immunosuppressive tumor microenvironment (TME). γδT cells, a subset of T cells with innate and adaptive immune functions, exhibit potent antitumor activity. Compared with γδT cells, Chimeric Antigen Receptor γδT (CAR-γδT) cells show enhanced tumor-targeting ability and superior efficacy in solid tumors, representing a promising strategy for GBM. Programmed Death Ligand 1 (PDL1), highly expressed on GBM cells and a key mediator of immunosuppressive TME, is an attractive target for GBM therapy. Here, we constructed three PDL1-targeted CAR-γδT cells using nanobodies (VHHs) with good binding ability and certain blocking functions. In vitro, these cells exhibited significant cytotoxicity against U87-MG and U138-MG cells, accompanied by the release of cytotoxic cytokines. Under repeated PDL1 antigen stimulation, all three PDL1-CAR-γδT cells continuously resisted tumor antigen while maintaining high activation and minimal exhaustion. In a cell-derived xenograft (CDX) mouse model, PDL1-CAR-γδT cells effectively suppressed GBM growth. These results suggest that PDL1-CAR-γδT cells represent a novel and promising therapeutic strategy for GBM.