Unraveling the immune landscape and molecular signatures of antibody-dependent cellular cytotoxicity in SARS-CoV-2 clearance
Beyond direct neutralization, antibodies clear SARS-CoV-2 by triggering antibody-dependent cellular cytotoxicity (ADCC), which guides natural killer (NK) cells to eliminate infected cells. To understand ADCC’s role in COVID-19, we analyze samples from primary patients and find that plasma ADCC activity correlated with a slower rate of viral clearance. To explore this mechanism, we isolate a monoclonal antibody with potent ADCC activity against SARS-CoV-2 variants. In infected mice, this antibody activates an antiviral transcriptional program in the lungs that suppresses viral RNA synthesis. Spatial transcriptomic analysis of mice treated with ADCC-mediating antibodies reveals that low expression of cytolytic NK cell markers and NK cell cluster-associated gene pathways are linked to pulmonary viral clearance. Furthermore, human peripheral NK cells activate pre-existing NK cell clusters when engaging the ADCC antibody. Our findings demonstrate that ADCC-mediating antibodies recruit NK subsets with low baseline cytolytic signatures to facilitate effective viral clearance. Spatial transcriptomics and CyTOF reveal that an isolated monoclonal ADCC antibody promotes SARS-CoV-2 clearance by recruiting specific NK subsets with low baseline cytolytic signatures and activated cluster-associated pathways.
Authors
- Dong-Yen Tsai
- I‐Ying Lin (ORCID: https://orcid.org/0000-0002-9805-6920)
- Takashi Angata (ORCID: https://orcid.org/0000-0002-4171-702X)
- Fang-Ju Chang (ORCID: https://orcid.org/0009-0003-1395-6714)
- Yi‐Ling Lin (ORCID: https://orcid.org/0000-0002-1838-6410)
- Kai Xuan Tin (ORCID: https://orcid.org/0009-0005-8880-7224)
- Wan-Chen Hsieh (ORCID: https://orcid.org/0000-0002-2555-6991)
- Chun‐Che Liao (ORCID: https://orcid.org/0000-0002-5153-4024)
- Wei-Nan Chen
- Wye‐Lup Kong (ORCID: https://orcid.org/0000-0002-4365-0105)
- Yi-Shiuan Tzeng
- Yu‐Chi Chou (ORCID: https://orcid.org/0000-0002-0783-1339)
- Mei‐Yeh Jade Lu (ORCID: https://orcid.org/0000-0002-4053-4889)
- Kuo‐I Lin (ORCID: https://orcid.org/0000-0003-4477-0798)
- Wenyu Chen (ORCID: https://orcid.org/0000-0001-8108-1778)
- Yi‐Hua Chen (ORCID: https://orcid.org/0000-0003-2464-2537)
- Shih‐Yu Chen (ORCID: https://orcid.org/0000-0002-7955-481X)
- Yi-Hsuan Chang
- Yen-Chen Chen
- Yi-Fu Wang (ORCID: https://orcid.org/0009-0003-2387-9353)
- Jia-Tsrong Jan
- Deepa Sridharan (ORCID: https://orcid.org/0000-0003-3517-8389)
- Szu-Teng Ma
- Ming-Tsan Liu
- Chih-Heng Huang
- Jian-Jong Liang
Institutions
- National Taiwan University (TW)
- Genomics Research Center, Academia Sinica (TW)
- Institute of Biological Chemistry, Academia Sinica (TW)
- Institute of Biomedical Sciences, Academia Sinica (TW)
- Biomedical Translation Research Center (TW)
- Ministry of Health and Welfare (TW)
- Biodiversity Research Center, Academia Sinica (TW)
- National Defense Medical Center (TW)
Publication Details
- Journal
- Communications Biology
- Published
- 2026-08-18
- DOI
- https://doi.org/10.1038/s42003-026-10789-6
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Academia Sinica
- Ministry of Science and Technology, Taiwan
- National Science and Technology Council