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Emerging evidence from animal studies and clinical observations suggests that peripheral immune responses amplify neuroinflammation after acute ischemic stroke. This review briefly summarizes the interactions between peripheral immune responses and the ischemic brain, with a focus on the brain\u2013spleen axis. Specifically, we dissect the mechanisms underlying spleen-mediated immune effects on the ischemic brain. We then critically summarize current spleen-targeted therapeutic strategies, ranging from physical and pharmacological interventions to stem cell-based approaches that reprogram splenic immune landscapes. 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