Checkpoint blockade-related CNS adverse events are characterized by neurotoxic T helper cells with sustained neuroantigen reactivity.

The immune-related adverse events of central nervous system (irAEs-CNS) are rare yet life-threatening complications arising from immune checkpoint inhibitor therapies, with no effective treatments. The intracranial immune landscape in irAE-CNS remains poorly characterized. Through longitudinal multi-omics profiling of cerebrospinal fluid from three independent clinical cohorts-combined with serial cerebral positron emission tomography/computed tomography (PET/CT) imaging, neurofunctional assessments, and 15-month clinical follow-up, we identify a defined proinflammatory memory T helper cell population specific to irAEs-CNS. These cells co-secrete six signature inflammatory mediators (poly6+ cells) linked to interleukin (IL)-17-driven pathways, exhibit persistent neuroantigen reactivity, and could induce neuron apoptosis. Notably, NMDAR1-specific poly6+ cells are correlated with intracranial inflammation states and clinical outcomes of the disease. Therapeutically, inhibition of IL-17-a key cytokine of poly6+ cells-significantly improves irAE-CNS outcomes without compromising overall survival rates. Our study uncovers neuroantigen-specific proinflammatory Th cells as central drivers of irAE-CNS pathogenesis, offering mechanistic insights and potential therapeutic targets for this debilitating condition.