Fanning the flames: IFN-γ fuels CAR-T inflammation and cytopenia.

Chimeric antigen receptor T cell (CAR-T) therapy has transformed the treatment of hematologic malignancies, yet, severe inflammatory toxicities continue to limit its broader use. In this issue of the JCI, Goala et al. uncovered a mechanistic link between IFN-γ-driven inflammation and disrupted neutrophil homeostasis, revealing that cytokine release syndrome (CRS) and immune cell-associated hematologic toxicity (ICAHT) stem from a shared biological pathway. Using IL-2Ra-deficient mice and patient samples, they showed that IFN-γ suppressed IL-17A and granulocyte colony-stimulating factor (G-CSF), disrupting granulopoiesis and neutrophil survival. Strikingly, IFN-γ blockade eased both CRS and neutropenia without diminishing CAR-T efficacy, suggesting a path toward safer, better-tolerated cell therapies.