This century has seen game-changing progress in the delivery of ab T cell–centric cancer immunotherapies, including immune checkpoint blockade, chimeric antigen receptor (CAR) T cells, tumor-infiltrating lymphocytes, and affinity-enhanced T cell receptors (TCRs) in soluble and membrane-bound forms. Empowered by years of research elucidating key aspects of ab T cell biology, clinicians have achieved notable rates of remission in patients with hitherto deadly diseases such as metastatic melanoma and multiple myeloma. However, there is much more to do. In particular, successful immunotherapy needs to reach increased numbers of patients of diverse ethnicities with a much broader range of tumor types. It needs to do so while incurring fewer adverse events and with the goal being complete cure. An emerging approach to achieving this ambition is to exploit γδ T cells, which first came to light about 40 years ago and comprise a distinct lymphocyte lineage that is mostly conserved across jawed vertebrates. Fundamental research has highlighted many aspects of γδ T cell biology that seem very well suited to cancer immunotherapy, including the cells’tropism for tissues in which solid tumors form, their very broad recognition potentials, their high tolerance of normal tissues, and their functional pleiotropy. In particular, γδ T cells seem able to combine highly specific adaptive responses with the rapidity and polyclonality of innate immunity, including a capacity to harness a battery of so-called natural killer receptors that target transformed cells. In this review, we consider these signature properties, their ongoing clinical application, and the emerging efficacy and safety readouts.
