Artificial Host-Guest Recognition Directs Glycometabolically Engineered Macrophages to Tumors

Area of Science:

• Immunology
• Biotechnology
• Cancer Research

Background:

• Chimeric antigen receptor macrophage (CAR-M) therapy faces challenges with genetic engineering complexity and maintaining anti-tumor activity in immunosuppressive tumor microenvironments.
• Current CAR-M therapies often rely on viral vectors, which can be complex and costly.
• Solid tumors present a difficult target for engineered immune cells due to the tumor microenvironment's immunosuppressive nature.

Purpose of the Study:

• To develop a non-viral, supramolecular glycoengineering strategy to enhance macrophage-based cancer therapy.
• To create glycoengineered supramolecular macrophages (GSAR-M) that bypass genetic modification.
• To investigate the efficacy of GSAR-M in targeting and eliminating tumor cells and remodeling the tumor microenvironment.

Main Methods:

• Utilized a metabolic labeling agent (Ac4ManNAda) to install adamantane (Ada) tags on macrophage surfaces via native biosynthetic pathways.
• Generated glycoengineered supramolecular macrophages (GSAR-M) capable of host-guest interactions with β-cyclodextrin (β-CD)-tagged tumor cells.
• Assessed GSAR-M activation, migratory, phagocytic, and tumoricidal capacities, including enhanced responses after LPS stimulation (GSAR-M+).
• Evaluated the therapeutic effect in a murine 4T1 breast cancer model.

Main Results:

• Supramolecular glycoengineering successfully generated GSAR-M with enhanced tumor cell recognition via CD-Ada host-guest interactions.
• GSAR-M exhibited an intrinsic activated state with upregulated markers and improved migratory, phagocytic, and tumoricidal functions.
• GSAR-M+ demonstrated superior tumor cell capture in vitro.
• In vivo studies showed profound tumor growth arrest and effective remodeling of the immunosuppressive tumor microenvironment in the 4T1 breast cancer model.

Conclusions:

• Established a streamlined, cost-effective, non-viral engineering paradigm for adoptive cell therapy.
• This supramolecular glycoengineering strategy integrates host-guest recognition with glycometabolic engineering.
• Provides critical insights for developing next-generation engineered immune cells for cancer treatment.