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An important activating receptor is Fc gamma receptor IIIa (Fc\u03b3RIIIA or CD16A), which can trigger antibody\u2010dependent cellular cytotoxicity (ADCC) when recognizing antibody\u2010opsonized target cells. One strategy to boost ADCC responses may be achieved by inhibiting activation\u2010induced shedding of CD16A from the NK cell surface. However, previous preclinical studies have shown contrasting results regarding the effectiveness and limitations of this approach. Here, microchip\u2010based live cell\u2010imaging was used to assess the consequences of CD16A shedding inhibition on the dynamics of NK cell cytotoxicity. The bispecific innate cell engager acimtamig (AFM13) was superior to IgG1 monoclonal antibodies in ADCC and in increasing the fraction of cytotoxic NK cells and serial killers. Under conditions where CD16A shedding was inhibited, acimtamig still triggered ADCC; however, the ability to promote serial killing was reduced and associated with impaired NK cell detachment from target cells. These results demonstrate that CD16A shedding represents an intrinsic feature of NK cell biology that is critical to sustain the antitumoral cytotoxicity of NK cells. This has implications for CD16A engineering of NK cell products and their combination with CD16A\u2010directed NK cell engagers.<\/jats:p>","DOI":"10.1002\/eji.70078","type":"journal-article","created":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T04:10:20Z","timestamp":1761019820000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["CD16A Shedding Regulates Innate Cell Engager\u2010Induced Serial Killing by Natural Killer Cells"],"prefix":"10.1002","volume":"55","author":[{"given":"Chiara","family":"Zambarda","sequence":"first","affiliation":[{"name":"Department of Applied Physics Science for Life Laboratory KTH Royal Institute of Technology  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karolin","family":"Guldevall","sequence":"additional","affiliation":[{"name":"Department of Applied Physics Science for Life Laboratory KTH Royal Institute of Technology  Stockholm 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