Membrane-Fusion-Mediated Multiplex Engineering of Tumor Cell Surface Glycans for Enhanced NK Cell Therapy

Area of Science:

• Immunology
• Biotechnology
• Cancer Therapy

Background:

• Natural killer (NK) cell therapies are promising for cancer treatment but face resistance due to immunosuppressive glycans on tumor cells.
• Effective cancer immunotherapy requires simultaneous reduction of inhibitory glycans and elevation of activating glycans on tumor surfaces.

Purpose of the Study:

• To develop a novel core-shell membrane-fusogenic liposome (MFL) system to simultaneously modify tumor cell surface glycans for enhanced NK cell activity.
• To reverse glycan-mediated immunosuppression and promote NK cell-mediated tumor elimination.

Main Methods:

• Designed MFLs loaded into a thermosensitive hydrogel for controlled local delivery to tumors.
• MFLs fuse with tumor cell membranes, delivering a sialyltransferase inhibitor to the cytoplasm and anchoring an NK-activating glycan shell to the surface.
• Spatially controlled delivery inhibits intracellular sialic acid production and presents NK-activating Lewis X trisaccharide (LeX) on the tumor surface.

Main Results:

• Successfully reprogrammed tumor cell surface glycans, downregulating immunosuppressive sialic acid and upregulating activating LeX.
• Achieved simultaneous physical modification and biological inhibition of immunosuppressing glycans via membrane fusion.
• Enhanced susceptibility of tumor cells to NK cell recognition and lysis.

Conclusions:

• The MFL platform effectively reverses glycan-mediated immunosuppression, transforming tumor cell surfaces from inhibitory to activating for NK cells.
• This approach offers a novel strategy for multiplex cell engineering and personalized regulation of intercellular interactions in cancer immunotherapy.
• Demonstrates potential for improved tumor elimination through enhanced NK cell-mediated cytotoxicity.