ORIGINAL RESEARCH article
Front. Immunol.
Sec. NK and Innate Lymphoid Cell Biology
This article is part of the Research TopicNovel Chimeric Antigen Receptor (CAR) Designs in engineering NK cells for CancerView all 11 articles
Construction of Anti-HER2 Affibody-Directed CAR-NK and Its Synergistic Effects with Doxorubicin-loaded Nanodrug Against HER2-Positive Breast Cancer
Provisionally accepted
- 1Second Hospital of Jiaxing City, Jiaxing, China
- 2Beijing University of Technology, Beijing, China
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Chimeric antigen receptor (CAR)-engineered T or natural killer (NK) cells are a promising approach for cancer immunotherapy. The leading region of the CAR structure is generally a single-chain antibody (scFv) fragment specific for a tumor cell surface molecule, and other structures are rarely reported. In this study, we developed a novel anti-human epidermal growth factor receptor 2 (HER2) CAR-NK cell using an affibody molecule as the extracellular targeting domain instead of the conventional scFv. These affibody-based CAR-NK cells, generated from the NK-92 cell line, demonstrated improved effective cytotoxicity against HER2-positive breast cancer cells, comparable to anti-HER2 scFv-based CAR-NK cells. Considering the clinical safety of the CAR-NK cell line, we found that 10 Gray (Gy) γ-irradiation inhibits the malignant proliferation. However, CAR-NK cell toxicity decreased significantly after irradiation. We thus combined affibody-based CAR-NK cells with doxorubicin (DOX)-loaded nanoparticles. Notably, the incorporation of DOX nanoparticles markedly enhanced the killing capacity of irradiated CAR-NK cells, restoring and even amplifying their antitumor efficacy. This synergistic effect underscores the potential of combining CAR-NK immunotherapy with chemotherapeutic nanomedicine. In summary, we demonstrate that affibody-based CAR-NK cells are a viable alternative to scFv-based constructs, and that their cytotoxicity-attenuated by irradiation, can be significantly enhanced through combination with DOX nanoparticles, offering a potent strategy for treating HER2-positive breast cancer.
Keywords: CAR-NK, NK92MI, Affibody, DOX, Nanoparticles
Received: 25 Aug 2025; Accepted: 15 Dec 2025.
Copyright: © 2025 He, Liang, Liu, Zhang, Liang, Jia and Sheng. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Hao Liang
Runqing Jia
Wang Sheng
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