Unleashing TNF cytotoxicity to enhance cancer immunotherapy

Tumor necrosis factor (TNF) is a proinflammatory cytokine that is produced andsecreted by cytotoxic lymphocytes upon tumor target recognition. Dependingon the context, TNF can mediate either pro-survival or pro-death signals. Thepotential cytotoxicity of T cell-produced TNF, particularly in the context of T celldirected immunotherapies, has been largely overlooked. However, a spate of recent studies investigating tumor immune evasion through the application of CRISPR-based gene-editing screens have highlighted TNF-mediated killing as an important component of the mammalian T cell antitumor repertoire. In the context of the current understanding of the role of TNF in antitumor immunity, we discuss these studies and touch on their therapeutic implications. Collectively, we provide an enticing prospect to augment…