The Diverse Roles of γδ T Cells in Cancer: From Rapid Immunity to Aggressive Lymphoma

Simple Summary:& nbsp;gamma delta T cells play important roles in cancer immunity. Their rapid activation and cytotoxic nature make them promising candidates for use in cell-based immunotherapies; however, under certain conditions, they can induce pro-tumour functions. Furthermore, upon transformation, gamma delta T cells can develop into aggressive lymphomas with a poor prognosis and no curative therapeutic options. Here, we provide a comprehensive summary of our current knowledge on the complex roles of gamma delta T cells in cancer. We discuss their anti- and pro-tumour functions in both solid and blood cancers, highlighting the key subsets involved and their potential utility in anti-cancer immunotherapy. We also discuss the mechanisms of gamma delta T-cell transformation, summarising the resulting gamma delta T-cell leukaemia/lymphoma entities and their genetic and molecular profiles, as well as current and future treatment strategies.& nbsp;gamma delta T cells are unique players in shaping immune responses, lying at the intersection between innate and adaptive immunity. Unlike conventional alpha beta T cells, gamma delta T cells largely populate non-lymphoid peripheral tissues, demonstrating tissue specificity, and they respond to ligands in an MHC-independent manner. gamma delta T cells display rapid activation and effector functions, with a capacity for cytotoxic anti-tumour responses and production of inflammatory cytokines such as IFN-gamma or IL-17. Their rapid cytotoxic nature makes them attractive cells for use in anti-cancer immunotherapies. However, upon transformation, gamma delta T cells can give rise to highly aggressive lymphomas. These rare malignancies often display poor patient survival, and no curative therapies exist. In this review, we discuss the diverse roles of gamma delta T cells in immune surveillance and response, with a particular focus on cancer immunity. We summarise the intriguing dichotomy between pro- and anti-tumour functions of gamma delta T cells in solid and haematological cancers, highlighting the key subsets involved. Finally, we discuss potential drivers of gamma delta T-cell transformation, summarising the main gamma delta T-cell lymphoma/leukaemia entities, their clinical features, recent advances in mapping their molecular and genomic landscapes, current treatment strategies and potential future targeting options.