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Specifically Editing Cancer Sialoglycans for Enhanced In Vivo Immunotherapy through Aptamer-Enzyme Chimeras
Qin Liu1, Hang Xing2, Mengyi Xiong1
1Molecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, 410082, Changsha, Hunan, P. R. China.
Abstract:
Immune checkpoint blockade (ICB) therapies have demonstrated remarkable clinical success in treating cancer. However, their objective response rate remains suboptimal because current therapies rely on limited immune checkpoints that fail to cover the multiple immune evasion pathways of cancer. To explore potential ICB strategies, we propose a glycoimmune checkpoint elimination (glycoICE) therapy based on targeted editing of sialoglycans on the tumor cell surface using an aptamer-enzyme chimera (ApEC). The ApEC can be readily generated via a one-step bioorthogonal procedure, allowing for large-scale and uniform production. It specifically targets and desialylates cancer cells, disrupting the sialoglycan-Siglec axis to activate immune cells and enhance immunotherapy efficacy, while its high tumor selectivity minimizes side effects from indiscriminate desialylation of normal tissues. Furthermore, the ApEC has the potential to be a versatile platform for specific editing of sialoglycans in different tumor models by adjusting the aptamer sequences to target specific protein markers. This research not only introduces a novel molecular tool for the effective editing of sialoglycans in complex environments, but also provides valuable insights for advancing DNA-based drugs towards in vivo and clinical applications.
Insights
Glycoimmune checkpoint elimination (glycoICE) therapy uses aptamer-enzyme chimeras to edit tumor cell surface sialoglycans, enhancing cancer immunotherapy. This novel approach disrupts immune evasion, boosting treatment efficacy with minimal side effects.
Area of Science:
- Biochemistry
- Immunology
- Oncology
Background:
- Immune checkpoint blockade (ICB) therapy shows promise in cancer treatment but has suboptimal response rates due to limited targeting of immune evasion pathways.
- Current ICB therapies do not address the multifaceted immune evasion strategies employed by cancer cells.
Purpose of the Study:
- To develop a novel immunotherapy strategy, glycoimmune checkpoint elimination (glycoICE), for enhanced cancer treatment.
- To create a versatile aptamer-enzyme chimera (ApEC) platform for targeted sialoglycan editing on tumor cells.
Main Methods:
- Generation of aptamer-enzyme chimeras (ApECs) via a one-step bioorthogonal procedure for large-scale production.
- Targeted desialylation of cancer cells by ApECs to disrupt the sialoglycan-Siglec axis and activate immune cells.
- Utilizing tumor-selective targeting of ApECs to minimize off-target effects on normal tissues.
Main Results:
- ApECs effectively target and desialylate cancer cells, disrupting the sialoglycan-Siglec axis.
- The glycoICE therapy demonstrated enhanced immune cell activation and improved immunotherapy efficacy.
- High tumor selectivity of ApECs was observed, minimizing side effects.
Conclusions:
- GlycoICE therapy represents a novel approach to overcoming cancer immune evasion by targeting sialoglycans.
- ApECs offer a versatile platform for DNA-based drug development and potential clinical applications in cancer immunotherapy.
- This strategy enhances immunotherapy efficacy by disrupting specific tumor-associated glycan structures.
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