A covalent peptide-based lysosome-targeting protein degradation platform for cancer immunotherapy

Area of Science:

• Biochemistry
• Immunology
• Oncology

Background:

• Lysosome-targeting chimeras (LYTACs) are effective for membrane protein degradation but face synthesis and tumor penetration challenges.
• Antibody-based LYTACs have limited ability to penetrate solid tumors and cross the blood-brain barrier (BBB).

Purpose of the Study:

• To develop a novel, modular peptide-based targeted degradation platform (Pep-TACs) for membrane protein degradation.
• To overcome the limitations of LYTACs in terms of synthesis, tumor penetration, and BBB crossing.

Main Methods:

• Designed covalent chimeric peptide-based targeted degradation platform (Pep-TACs) with a flexible aryl sulfonyl fluoride group.
• Utilized transferrin receptor (TFRC)-mediated lysosomal targeted endocytosis for protein degradation.
• Evaluated Pep-TACs efficacy in degrading PD-L1, enhancing T cell function, and promoting macrophage phagocytosis in tumor models, including brain tumors.

Main Results:

• Pep-TACs significantly degraded PD-L1 expression on various immune cells and tumor cells, particularly in acidic tumor microenvironments.
• Demonstrated enhanced T cell function and macrophage-mediated tumor phagocytosis.
• Achieved significant anti-tumor immune responses in both anti-PD-1-responsive and -resistant models.
• Showed that Pep-TACs can cross the BBB and prolong survival in mice with in situ brain tumors.

Conclusions:

• Introduced a modular TFRC-based covalent peptide degradation platform (Pep-TACs) for efficient membrane protein degradation.
• Pep-TACs offer a promising strategy for immunotherapy, especially for brain tumors, due to their BBB penetration and efficacy.
• The platform facilitates targeted protein degradation and enhances anti-tumor immune responses.