CAR T cell–derived TNF is an early determinant of cytokine release syndrome severity

Cytokine release syndrome (CRS) is a common and potentially severe toxicity of chimeric antigen receptor (CAR) T cell therapy, characterized by activation of the host myeloid compartment and systemic inflammation. Although downstream effectors such as interleukin-6 (IL-6) and IL-1β 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-derived 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-1β. We further show that TNF is a determinant of CRS severity in humanized xenochimeras, governing the overall disease course including eventual lethality. Our findings thus identify TNF as an upstream regulator of CRS acting at least in part via the host macrophage compartment.