Harnessing Self-Assembling Peptides on γδ T Cells to Enhance Anti-Tumor Immunity.

γδ T cells possess significant anti-tumor potential; however, the expression of immune checkpoint molecules on tumor cells often leads to functional exhaustion of these T cells, resulting in variable outcomes in clinical trials. Targeting these immune checkpoints may alleviate the inhibitory effects of the tumor microenvironment on γδ T cell functionality. In this study, we developed a PD-L1-targeting peptide conjugated with maleimide, facilitating self-assembly on the surface of γδ T cells to form fibrous structures via Michael addition reactions with thiol groups on the cell membrane. Our findings demonstrate that this peptide effectively binds and self-assembles without impairing the proliferation or effector functions of γδ T cells. Notably, peptide-modified γδ T cells exhibited enhanced cytotoxic activity against tumor cells in vitro and significantly inhibited tumor growth in vivo. Furthermore, these modified γδ T cells promoted the infiltration of CD8+ T cells and M1 macrophages into the tumor microenvironment. These results indicate that peptide-modified γδ T cells not only inhibit tumor progression but also mitigate the suppressive effects of the tumor microenvironment, thereby enhancing the synergistic anti-tumor responses of other immune cells. This research presents a straightforward and effective strategy for improving the immunosuppressive tumor microenvironment and augmenting the anti-tumor efficacy of γδ T cells.