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Updated: Jul 17, 2025
Advances in Human Induced Pluripotent Stem Cell-Derived Chimeric Antigen Receptor-Expressing Natural Killer Cells
Published on: February 14, 2025
Natural killer cells modified with a Gpc3 aptamer enhance adoptive immunotherapy for hepatocellular carcinoma
Youshi Zheng1,2, Zisen Lai1, Bing Wang1,2
1The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, People's Republic of China.
Introduction:
Natural killer cells can attack cancer cells without prior sensitization, but their clinical benefit is limited owing to their poor selectivity that is caused by the lack of specific receptors to target tumor cells. In this study, we aimed to endow NK cells with the ability to specifically target glypican-3+ tumor cells without producing cell damage or genetic alterations, and further evaluated their therapeutic efficiency.
Methods:
NK cells were modified with a Gpc3 DNA aptamer on the cell surface via metabolic glycoengineering to endow NK cells with specific targeting ability. Then, the G-NK cells were evaluated for their specific targeting properties, cytotoxicity and secretion of cytokines in vitro. Finally, we investigated the therapeutic efficiency of G-NK cells against glypican-3+ tumor cells in vivo.
Results:
Compared with NK cells modified with a random aptamer mutation and unmodified NK cells, G-NK cells induced significant apoptosis/necrosis of GPC3+ tumor cells and secreted cytokines to preserve the intense cytotoxic activities. Moreover, G-NK cells significantly suppressed tumor growth in HepG2 tumor-bearing mice due to the enhanced enrichment of G-NK cells at the tumor site.
Conclusions:
The proposed strategy endows NK cells with a tumor-specific targeting ability to enhance adoptive therapeutic efficiency in GPC3+ hepatocellular carcinoma.
Insights
This study engineered natural killer (NK) cells to specifically target glypican-3 positive (GPC3+) tumors using DNA aptamers. Engineered G-NK cells demonstrated enhanced tumor cell killing and suppressed tumor growth in vivo.
Area of Science:
- Immunology
- Biotechnology
- Cancer Therapy
Background:
- Natural killer (NK) cells possess inherent anti-cancer properties but lack tumor-specific targeting, limiting their clinical efficacy.
- Current limitations in NK cell therapy stem from poor selectivity and off-target effects.
- Developing targeted NK cell therapies is crucial for improving cancer treatment outcomes.
Purpose of the Study:
- To engineer NK cells to specifically target glypican-3 (GPC3)+ tumor cells.
- To evaluate the therapeutic potential of GPC3-targeted NK cells without causing genetic alterations or cell damage.
- To assess the in vitro and in vivo efficacy of the engineered NK cells.
Main Methods:
- Metabolic glycoengineering was used to modify NK cells with a GPC3 DNA aptamer, creating G-NK cells.
- In vitro assays assessed G-NK cell targeting specificity, cytotoxicity, and cytokine secretion.
- In vivo studies evaluated the therapeutic efficacy of G-NK cells in a GPC3+ tumor xenograft mouse model.
Main Results:
- G-NK cells exhibited specific targeting and induced significant apoptosis/necrosis in GPC3+ tumor cells.
- Engineered NK cells maintained potent cytotoxic activities and secreted cytokines.
- G-NK cells significantly suppressed tumor growth in vivo, with enhanced accumulation at the tumor site.
Conclusions:
- The developed strategy successfully endowed NK cells with tumor-specific targeting capabilities for GPC3+ malignancies.
- This approach enhances the adoptive therapeutic efficiency of NK cells against GPC3+ hepatocellular carcinoma.
- Targeted NK cell engineering offers a promising avenue for improving cancer immunotherapy.
