Unleashing TNF cytotoxicity to enhance cancer immunotherapy

Tumor necrosis factor (TNF) is a proinflammatory cytokine that is produced and secreted by cytotoxic lymphocytes upon tumor target recognition. Depending on the context, TNF can mediate either pro-survival or pro-death signals. The potential cytotoxicity of T cell-produced TNF, particularly in the context of T cell-directed 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 immunotherapy responses through TNF cytotoxicity. Cancer immunotherapy aims to enhance antitumor T cell cytotoxicity. Inflammatory cytokines are a part of the cytotoxic T cell arsenal; however, their cytotoxic activity is largely overlooked in the context of immunotherapy.TNF is one such inflammatory cytokine that can signal either pro-survival or pro-death signals depending on the context.Interest in TNF in the immunotherapy field has been reinvigorated by a recent collection of loss-of-function genetic screens in tumor cells, and these have highlighted multiple components of the TNF signaling pathway that can be protective against CD8+ T cell cytotoxicity.Pharmacological targeting of several proteins identified in these preliminary screens might provide a means to reroute tumor TNF signaling towards pro-death, representing a new combinatorial strategy to exploit T cell-derived TNF and boost responses to immunotherapy.