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

CAR T cell-derived TNF is a key early driver of cytokine release syndrome severity, influencing disease progression and lethality in mouse and humanized models.

• Why it matters: CRS is a serious side effect of CAR T cell therapy, but the initial signals triggering it are not fully understood, limiting targeted interventions to improve safety.
• What they did: Researchers disrupted TNF signaling in a mouse model of CRS and observed that CAR T cell-produced TNF promotes pro-inflammatory macrophage accumulation and cytokine production, including IL-6 and IL-1β, affecting disease severity.
• The result: Blocking TNF reduced CRS severity and lethality, highlighting TNF as an upstream regulator that could be targeted to mitigate CRS in CAR T cell therapies.