γδ T cells and the PD-1/PD-L1 axis: a love-hate relationship in the tumor microenvironment

Gamma delta (gamma delta) T cells demonstrate strong cytotoxicity against diverse cancer cell types in an MHC-independent manner, rendering them promising contenders for cancer therapy. Although amplification and adoptive transfer of gamma delta T cells are being evaluated in the clinic, their therapeutic efficacy remains unsatisfactory, primarily due to the influence of the immunosuppressive tumor microenvironment (TME). Currently, the utilization of targeted therapeutic antibodies against inhibitory immune checkpoint (ICP) molecules is a viable approach to counteract the immunosuppressive consequences of the TME. Notably, PD-1/PD-L1 checkpoint inhibitors are considered primary treatment options for diverse malignancies, with the objective of preserving the response of alpha beta T cells. However, gamma delta T cells also infiltrate various human cancers and are important participants in cancer immunity, thereby influencing patient prognosis. Hence, it is imperative to comprehend the reciprocal impact of the PD-1/PD-L1 axis on gamma delta T cells. This understanding can serve as a therapeutic foundation for improving gamma delta T cells adoptive transfer therapy and may offer a novel avenue for future combined immunotherapeutic approaches.