γδ T Cells for Cancer Immunotherapy: Unconventional Players Take the Spotlight

The success of cancer immunotherapy depends on the mobilization of leukocytes with the capacity to eliminate tumor cells. γδ T cells represent a lymphocyte lineage with strong cytotoxic potential and abundant production of antitumor cytokines. Importantly, they are not restricted to MHC-mediated presentation of neoantigens and thus are highly suited to tackle major challenges in current immunotherapies. In this article, we review the main approaches to engage and expand γδ T cells endogenously (in patients) or exogenously (for adoptive cell therapy) against cancer. We discuss the dichotomy between activation and exhaustion of γδ T cells and how they may benefit from immune checkpoint blockade. Finally, we describe the biological properties of the two main subsets of human γδ T cells, Vδ1 and Vδ2 T cells, and how they are boosted, through genetic engineering, toward maximization of their performance as next-generation cancer immunotherapies.