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Although downstream effectors such as interleukin-6 (IL-6) and IL-1\u03b2 are well-characterized, the upstream signals that initiate CRS remain incompletely understood. By selectively disrupting tumor necrosis factor (TNF) signaling in a mouse model of CRS, we show that CAR T cell\u2013derived TNF promotes the accumulation of pro-inflammatory monocyte-derived macrophages at the tumor site and the induction of host-derived cytokines including IL-6 and IL-1\u03b2. We further show that TNF is a determinant of CRS severity in humanized xenochimeras, governing the overall disease course including eventual lethality. 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