Cancer immunotherapy has transformed oncology, but it can cause cognitive dysfunction. Geraghty, Acosta-Alvarez et al. now dissect the neuro-immune mechanisms behind these impairments.

In mouse models of cancer, chimeric antigen receptor (CAR)-T cell therapy impaired performance in tests of attention and memory. The treated mice had elevated levels of cytokines and chemokines in the cerebrospinal fluid, increased white matter microglial reactivity and — in line with the known effects of reactive microglia on CNS cells — reductions in oligodendroglial cell numbers and hippocampal neurogenesis. These findings were corroborated by single-nucleus RNA sequencing of post-mortem frontal lobe tissue samples from clinical trial participants treated with CAR-T cell therapy, which revealed transcriptomic changes indicative of altered microglial reactivity and oligodendroglial function.