Harnessing the potential of γδ T cells through engineering and combination treatment for cancer therapies

γδT cells comprise 1-10% of circulating T cells, are further enriched in barrier tissues such as the gut and skin, and also form a critical component of lymphoid stress surveillance. γδ T cells have been gaining prominence as an alternative to αβ T cells for cancer immunotherapy. Such popularity may be attributed to multiple factors including the MHC-independent nature of γδ T activation, which differentiates them from αβ T cells and underlies their lack of alloreactivity. In this Review, we describe efforts to optimize the potential of γδ T cells as a cancer immunotherapeutic. We discuss the impact of disease burden on efficacy and the contexts in which unmodified γδ T cells have succeeded or failed to yield durable responses. Finally, we explore options for enhancing γδ T cell efficacy including combinations with other treatments and engineering strategies to capitalize on their potency. Adoptive cell transfer therapies using αβ T cells have made strides in medical translation, but the application of γδ T cells remains a work-in-progress. Here the authors summarize the unique biological properties, means of engineering, regime for treatment, and future research directions that may help realize γδ T cells’ potential for the clinics.