TNF and neoplasm: Cytokine release syndrome, for example, has been reported as dose-limiting toxicity of systemic LCL161 administration in humans and is most likely attributable to SM-induced, NFκB-mediated upregulation of pro-inflammatory cytokines (including TNF).31 However, artificially establishing (transient) hypertonic conditions in a narrowly defined area such as the tumor environment could attenuate systemic toxicity by spatially restricting TNF production and lowering SM concentrations necessary for cancer cell elimination (Figures 1g and h and 3d–f).