Abstract
ABSTRACT
Immune checkpoint inhibitors (ICIs) targeting CTLA‐4 and PD‐1 have transformed cancer therapy, yet their immune‐related adverse events (irAEs) in various tissues, including the brain, remain poorly defined. ICI perturbs hippocampal‐dependent memory function by derailing neuro‐immune homeostasis and compromising synaptic integrity. However, the cellular and molecular mechanisms by which ICI alters regional interactions are not well understood. Using bulk RNA‐sequencing and MERFISH spatial transcriptomics in a syngeneic murine melanoma model, we show that ICI treatment remodels hippocampal gene expression and cellular organization. While tumor burden itself altered brain physiology, ICI distinctly modified the abundance and transcriptional states of neurons, microglia, astrocytes, oligodendrocytes, and T cells, with coordinated induction of inflammatory, synaptic, and immune‐response programs. Complementary analysis of human postmortem brain samples confirmed microglial activation as a key hallmark of ICI‐treated brains, highlighting the translational relevance of our findings. Finally, using a conditional deletion model, we show that T cells are indispensable for ICI‐driven microglial activation. Altogether, our results identify a T cell–microglia crosstalk axis as a driving mechanism of the pathophysiology of irAEs in the brain and provide a high‐resolution spatial model for better understanding neuroinflammatory responses during ICI‐induced unleashing of anti‐tumor immunity.