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The need of an autologous cell product poses scientific and logistical challenges that need to be overcome to develop efficacious, scalable and cost-effective ACT. Peripheral blood lymphocytes procured from healthy donors can serve as a starting population for manufacturing a universal allogeneic T cell product offering solutions to both challenges. Recent advances in gene-engineering and -editing technologies have facilitated progress in the development and large-scale manufacturing of allogeneic T cell products. A strategy in development of allogenic ACT is ablation of the TCR\u03b1\u03b2\/CD3 complex to avoid graft versus host disease mediated by unrelated donor T cells. Mitigating host allogeneic T cells recognition is a complex endeavor that may begin with HLA-I\/-II ablation, avoiding recognition and rejection of \u201cnon-self\u201d HLA molecules. However, HLA-deficient T cells are susceptible to host NK cell recognition via the \u201cmissing-self\u201d response. Here, we discuss immune evasive strategies taken to reduce NK cell mediated rejection of HLA-deficient T cells with particular emphasis on exploitation of HLA-E, a non-classical HLA-I, with regulatory function on NK cell activity. Current progress suggests that off-the-shelf universal T cell products may evolve to become a standard of care treatment options for certain disease indications.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1826738","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T05:47:40Z","timestamp":1779256060000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Designing universal T cell therapies: strategies to evade natural killer cells"],"prefix":"10.3389","volume":"17","author":[{"given":"Omar","family":"Bushara","sequence":"first","affiliation":[{"name":"Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania","place":["Philadelphia, PA, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gerald P.","family":"Linette","sequence":"additional","affiliation":[{"name":"Center for Cellular Immunotherapies, Perelman School of 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