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For development of economical off\u2010the\u2010shelf allogeneic therapies, maximal expansion of the NK cells from each donor must be achieved while maintaining efficacy and uniformity of the cell product. The standard method for robust expansion utilizes weekly stimulation with engineered feeder cells derived from the K562 cell line. However, the effects of repeated stimulation on NK cell growth, metabolism, and function are not well understood. In this study, we demonstrated a distinct shift in growth kinetics and metabolism around week 3\u20134 of repeated K562 feeder cell stimulation, followed by a change in cytokine secretion and killing ability. Seahorse metabolic flux assays and transcriptomics suggested a transition from glycolytic metabolism to oxidative metabolism after the first week of stimulation, but the shift in growth kinetics generally correlated to reduced metabolic activity. Collectively, these results indicate that serial stimulation sustains large\u2010fold NK cell expansion that can be exploited for NK cell therapy; however, this expansion has important impacts on NK cell growth, metabolism, and function. Careful characterization is critical when developing large\u2010scale biomanufacturing processes to ensure efficacy of the final cellular product.<\/jats:p>","DOI":"10.1002\/btpr.70100","type":"journal-article","created":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T07:49:26Z","timestamp":1768376966000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dynamics of natural killer cell function upon recurrent stimulation"],"prefix":"10.1002","volume":"42","author":[{"given":"Jennifer","family":"One","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering University of Minnesota  Minneapolis Minnesota USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janani","family":"Narayan","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering and Materials Science University of Minnesota  Minneapolis Minnesota 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