TNF-alpha: Roles in pathogenesis and therapeutics in cancer

Tumor necrosis factor alpha (TNF-α) is a pleiotropic cytokine that can both facilitate tumor progression and directly mediate tumor cell killing. This dual role creates a conundrum in which TNF can be either beneficial or detrimental for a tumor, depending on the context. Herein, we describe the history of the cytokine, the cases in which TNF-α has been considered as a cancer immunotherapy, and the toxicities that can manifest from its use. We also add context to its activity, particularly in T cells (via the engagement of TNF receptors) as well as the epigenetic and immunoregulatory pathways that are elicited. Furthermore, we highlight the fundamental differences in the transcriptional and translational regulation of this cytokine, which plays a significant role in the context of malignancy and potential success of immunotherapies. This review aims to provide insight and background on molecular switches, cellular context, and TNF receptor dynamics that determine the role of TNF-α as both tumor suppressor and promoter in different models, which is essential for deriving maximal benefit from TNF therapies.