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ICI perturbs hippocampal\u2010dependent memory function by derailing neuro\u2010immune homeostasis and compromising synaptic integrity. However, the cellular and molecular mechanisms by which ICI alters regional interactions are not well understood. Using bulk RNA\u2010sequencing 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\u2010response programs. Complementary analysis of human postmortem brain samples confirmed microglial activation as a key hallmark of ICI\u2010treated brains, highlighting the translational relevance of our findings. Finally, using a conditional deletion model, we show that T cells are indispensable for ICI\u2010driven microglial activation. Altogether, our results identify a T cell\u2013microglia crosstalk axis as a driving mechanism of the pathophysiology of irAEs in the brain and provide a high\u2010resolution spatial model for better understanding neuroinflammatory responses during ICI\u2010induced unleashing of anti\u2010tumor immunity.<\/jats:p>","DOI":"10.1002\/advs.77733","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T08:32:46Z","timestamp":1790757166000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Spatial Transcriptomics Reveals a T Cell\u2010Mediated Microglial Activation Axis of Immune Checkpoint Inhibition\u2010Related Adverse Events in the Brain"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0661-3524","authenticated-orcid":false,"given":"Devyani","family":"Swami","sequence":"first","affiliation":[{"name":"Department of Anatomy &amp; Neurobiology, School of Medicine 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