Specifically Editing Cancer Sialoglycans for Enhanced Immunotherapy In Vivo through Aptamer-Enzyme Chimeras

Abstract

Immune checkpoints blockade (ICB) therapies have demonstrated remarkable clinical success in treating cancer. However, its objective response rate remains suboptimal because current therapies rely on limited immune checkpoints that failed to cover the multiple immune evasion pathways of cancer. To explore potential ICB strategies, herein, we propose a glycoimmune checkpoint elimination (glycoICE) therapy depending on targeted edition of sialoglycans on tumor cell surface using aptamer-enzyme chimera (ApEC). The ApEC is readily generated via a one-step bioorthogonal procedure, allowing for large-scale and uniform production. The ApEC is able to target and desialylate cancer cells, leading to the elimination of sialoglycan-Siglec axis, which in turn activates immune cells and enhances immunotherapy efficiency. In addition to its remarkable therapeutic efficiency, the ApEC exhibits high tumor selectivity, which helps to avoid side effects caused by indiscriminate desialylation of normal tissues. Furthermore, the ApEC has the potential to be a versatile platform for specifical editing of sialoglycans in different tumor models by adjusting the aptamer sequences targeting associated with 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.