Multimodal targeting chimeras enable integrated immunotherapy leveraging tumor-immune microenvironment.

Area of Science:

• Oncology
• Immunology
• Biotechnology

Background:

• Immunotherapy has transformed cancer treatment but faces challenges due to tumor-immune microenvironment (TIME) complexity.
• Simultaneously engaging multiple immune cells in TIME is crucial but difficult.

Purpose of the Study:

• To develop a multimodal and programmable platform for integrating multiple therapeutic modules into single agents.
• To enable tumor-targeted co-engagement of diverse immune cells within the TIME.

Main Methods:

• Developed triple orthogonal linker (T-Linker) technology to create multimodal targeting chimeras (Multi-TACs).
• Integrated various therapeutic small molecules and biomolecules into Multi-TACs.
• Constructed Multi-TACs to coordinate T cells with other immune cell types.

Main Results:

• Demonstrated excellent efficacy of an EGFR-CD3-PDL1 Multi-TAC in targeting solid tumors via T-dendritic cell co-engagement.
• Validated efficacy in vitro, humanized mouse models, and patient-derived tumor models.
• Showcased the ability of Multi-TACs to coordinate T cells with other immune cells.

Conclusions:

• The developed Multi-TACs platform offers a promising strategy for synergistic cancer immunotherapy.
• The modular and programmable nature of Multi-TACs has broad potential applications in immunotherapy and beyond.