"ADCC involves the binding of antibody-coated infected cells with effector cells, particularly NK cells, through the Fc receptor, triggering granzyme and perforin release to induce target cell apoptosis. ADCC is a crucial component of antiviral immunity against several viruses, such as influenza virus, HIV, and dengue virus. Recent studies have demonstrated that ADCC contributes to immune responses against COVID-19. ADCC activity in plasma was higher in patients with severe COVID-19 than in asymptomatic and mild patients. Moreover, the importance of antibody effector functions was shown in mice lacking FcγR. However, the precise molecular and cellular mechanisms underlying ADCC-mediated immunity remain largely underexplored. In the current study, we sought to identify the NK cell subsets associated with ADCC by analyzing the immune cell profile and ADCC activity by cytometry by time of flight (CyTOF) analysis with human PBMC samples from convalescent individuals during the wild-type (WT) SARS-CoV-2 pandemic. We further studied transcriptomic changes of lung tissues elicited by ADCC during SARS-CoV-2 infection in vivo by employing an identified monoclonal antibody with ADCC-mediated protection activity. To further understand the spatial organization and activity of NK cell subsets, we performed spatial transcriptomic analysis and explored the cellular and molecular mechanisms of NK cell-mediated ADCC activity."