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In a longitudinal study of patients with malaria in a nonendemic setting, we observed a transient but potent activation of NK cell cytotoxicity during acute malaria, characterized by rapid granzyme B\u2013mediated killing and elevated expression of genes associated with cytotoxicity (\n                    <jats:italic>PRF1<\/jats:italic>\n                    ,\n                    <jats:italic>GZMB<\/jats:italic>\n                    , and\n                    <jats:italic>GZMA<\/jats:italic>\n                    ). This heightened activity was supported by increased plasma levels of granzymes and proinflammatory cytokines, which enhanced NK cell function in vitro. However, plasma samples from clinical malaria also contained inhibitory mediators, including soluble cytokine receptors, which dampened NK cell responses. These findings reveal that the host microenvironment orchestrates a tightly regulated NK cell response that potentiates cytotoxicity during acute infection and rapidly downmodulates it after treatment. Understanding this balance between activation and suppression may inform strategies to harness NK cells for malaria control while minimizing immunopathology.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.198687","type":"journal-article","created":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T17:35:17Z","timestamp":1776792917000},"source":"Crossref","is-referenced-by-count":4,"title":["NK cell cytotoxicity is transiently enhanced during acute malaria and modulated by the host microenvironment"],"prefix":"10.1172","volume":"11","author":[{"given":"Pengjun","family":"Xi","sequence":"first","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine Solna, Stockholm, Sweden."},{"name":"Department of Infectious Diseases and"},{"name":"Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick 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