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Background Antibody-dependent cellular cytotoxicity (ADCC) is a key mechanism of action for many therapeutic antibodies, mediated through engagement of Fcγ receptors on natural killer (NK) cells. This pathway underpins the efficacy of agents such as trastuzumab in HER2-positive cancers. However, most traditional preclinical models—such as 2D cell lines and spheroids—lack the complexity of human tumors, limiting their ability to predict ADCC activity and therapeutic response in patients.Methods To address this, Champions Oncology developed a translational ADCC evaluation platform using patient-derived xenograft organoids (PDXOs) derived from a biobank of over 1,500 solid and hematologic tumors. Mouse stromal components are depleted to generate pure human tumor organoids. Organoids from HER2-positive breast cancer PDXs were luciferase-labeled and seeded in 96-well plates. After spheroid formation, primary human NK cells were co-cultured with the organoids at optimized effector-to-target (E:T) ratios. A panel of HER2-targeting antibodies with intact Fc regions—including trastuzumab—and isotype and payload-only controls were tested. Tumor cell killing was quantified via luminescence.Results The assay showed high sensitivity and reproducibility, with robust Z′-factors and dynamic range. ADCC activity varied based on antibody format and Fc engagement. The platform effectively captured functional differences in NK-mediated cytotoxicity, highlighting pharmacologic distinctions between isotype controls, free payloads, and intact ADCs. Importantly, the 3D organoid format preserved tumor heterogeneity and microenvironmental features that influence ADCC response, which are often lost in 2D cultures.Conclusions Champions Oncology’s ADCC organoid co-culture system provides a physiologically relevant, scalable model for evaluating Fc-competent antibodies. By maintaining human tumor complexity and enabling detailed assessment of NK function and tumor susceptibility, this platform supports mechanistic studies, optimization of ADC design, and preclinical screening of antibody-based immunotherapies.