{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T12:25:18Z","timestamp":1784291118617,"version":"3.55.0"},"reference-count":64,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T00:00:00Z","timestamp":1778198400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>The adoptive transfer of NK cells has shown clinical promise in hematologic malignancies, but its efficacy in solid tumors remains limited. Three-dimensional (3D) models reproduce tumor architecture and immunosuppressive microenvironments more accurately than conventional two-dimensional (2D) cultures. Here, we employed colorectal cancer (CRC) and lung cancer 3D tumor models to evaluate the anti-tumor activity of cytokine-induced memory-like (CIML) NK cells and to test whether cetuximab augments these responses through antibody-dependent cellular cytotoxicity (ADCC). Human NK cells were preactivated overnight with interleukin (IL)-12\/15\/18 (pre-CIML), then co-cultured with tumor spheroids and patient-derived organoids in the presence or absence of cetuximab. Pre-CIML NK cells showed significantly enhanced effector functions compared to control NK cells, including increased degranulation, higher IFN-\u03b3 and TNF-\u03b1 production, and superior cytotoxicity against both spheroids and organoids. Additionally, pre-CIML NK cells that infiltrated tumor spheroids displayed a more uniform distribution within the tumor mass than control NK cells, which may contribute to their improved killing capacity. Cetuximab-mediated ADCC further enhanced NK cell activity against spheroid models, while in organoids, the enhancement was tumor- and context-dependent. Overall, these findings demonstrate that pre-CIML NK cells exhibit robust anti-tumor activity in clinically relevant 3D tumor models, and identify ADCC as an additional, but context-restricted, mechanism by which targeted antibodies such as cetuximab can further enhance NK cell functionality. These findings underscore the translational potential of NK cell-based immunotherapies that combine cytokine preactivation and ADCC induction to overcome current challenges in the treatment of solid tumors.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1797290","type":"journal-article","created":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T05:52:14Z","timestamp":1778219534000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Cytokine preactivation and ADCC: a potent strategy for enhancing human NK cell effector functions against 3D tumor models"],"prefix":"10.3389","volume":"17","author":[{"given":"Ainara","family":"Lopez-Pardo","sequence":"first","affiliation":[{"name":"Immunopathology Group, Biobizkaia Health Research Institute","place":["Barakaldo, 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