Membrane-immobilized gemcitabine for cancer-targetable NK cell surface engineering

Area of Science:

• Immunology
• Biotechnology
• Oncology

Background:

• Natural killer (NK) cell-based adoptive cell transfer (ACT) shows promise for cancer immunotherapy but faces limitations in solid tumors due to the immunosuppressive tumor microenvironment (TME).
• Current combinatorial therapies using chemotherapy and NK cells struggle with inefficient drug delivery and off-target toxicity.

Purpose of the Study:

• To develop a novel drug delivery system using NK cells to enhance the efficacy of cancer immunotherapy.
• To engineer NK cells with gemcitabine (Gem) conjugates to improve targeted drug delivery and overcome TME-related limitations.

Main Methods:

• Developed modular cell membrane-immobilized Gem conjugates (lipid-Gem conjugates) for NK cell surface engineering.
• Utilized a lipid anchor, poly(ethylene glycol), a disulfide bond cleavable linker, and Gem.
• Coated NK cells with lipid-Gem conjugates to create Gem-conjugated NK (GCNK) cells and evaluated their properties and anti-tumor efficacy against pancreatic cancer cells (PANC-1).

Main Results:

• NK cell proliferation and surface ligand availability were preserved after conjugation.
• GCNK cells demonstrated enhanced anti-tumor efficacy against PANC-1 cells.
• Gem was effectively released and upregulated MHC class I-related chain A and B on cancer cells, leading to enhanced NK cell activation and anti-tumor effects.

Conclusions:

• Simultaneous co-delivery of membrane-immobilized Gem with NK cells offers a promising strategy to enhance conventional ACTs.
• This approach facilitates immune synapse-mediated cancer recognition and chemotherapeutic effects, improving anti-cancer efficacy.