Silva-Santos et al. review γδ T cells in cancer, describing their potential for both antitumor functions (direct targeting of tumors via NKG2D-activated cytotoxicity or antibody-dependent cellular cytotoxicity; indirect targeting by impacting other cells in the TME) and pro-tumor functions (IL-17A production, immunosuppression). Strategies to utilize γδ T cells in immunotherapy include modulating their recruitment, enhancing or suppressing functions in particular subsets, harnessing cells for adoptive transfer or production of CAR γδ T cells, or transferring Vγ9Vδ2 TCRs into αβ T cells, but preclinical and clinical challenges remain.
The potential of cancer immunotherapy relies on the mobilization of immune cells capable of producing antitumour cytokines and effectively killing tumour cells. These are major attributes of gammadelta T cells, a lymphoid lineage that is often underestimated despite its major role in tumour immune surveillance, which has been established in a variety of preclinical cancer models. This situation notwithstanding, in particular instances the tumour microenvironment seemingly mobilizes gammadelta T cells with immunosuppressive or tumour-promoting functions, thus emphasizing the importance of regulating gammadelta T cell responses in order to realize their translation into effective cancer immunotherapies. In this Review we outline both seminal work and recent advances in our understanding of how gammadelta T cells participate in tumour immunity and how their functions are regulated in experimental models of cancer. We also discuss the current strategies aimed at maximizing the therapeutic potential of human gammadelta T cells, on the eve of their exploration in cancer clinical trials that may position them as key players in cancer immunotherapy.