Filling the tank: Keeping antitumor T cells metabolically fit for the long haul

Discoveries in tumor immunology and subsequent clinical advances in cancer immunotherapy have revealed that the immune system is not oblivious to tumor progression but heavily interacts with developing neoplasia and malignancy. A major factor preventing immune destruction is the establishment of a highly immunosuppressive tumor microenvironment (TME), which provides architecture to the tumor, supports indirect means of immunosuppression such as the recruitment of tolerogenic cells like regulatory T cells and myeloid-derived suppressor cells (MDSC), and represents a zone of metabolically dearth conditions. T-cell activation and consequent effector function are cellular states characterized by extreme metabolic demands, and activation in the context of insufficient metabolic substrates results in anergy or regulatory differentiation. Thus, T cells must endure both immunosuppression (co-inhibitory molecule ligation, regulatory T cells, and suppressive cytokines) but also a sort of metabolic suppression in the TME. Here I will review the general features of the TME, identify the metabolic demands of activated effector T cells, discuss the known metabolic checkpoints associated with intratumoral T cells, and propose strategies for generating superior antitumor T cells, whether in vitro for adoptive cell therapy or through in vivo reinvigoration of the existing immune response.