Faculty, Staff and Student Publications

Language

English

Publication Date

3-1-2025

Journal

Nature Cancer

DOI

10.1038/s43018-025-00919-0

PMID

40000910

PMCID

PMC11952976

PubMedCentral® Posted Date

9-1-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

Antigen-presenting cells phagocytose tumor cells and subsequently cross-present tumor-derived antigens. However, these processes are impeded by phagocytosis checkpoints and inefficient cytosolic transport of antigenic peptides from phagolysosomes. Here, using a microbial-inspired strategy, we engineered an antibody-toxin conjugate (ATC) that targets the 'don't eat me' signal CD47 linked to the bacterial toxin listeriolysin O from the intracellular bacterium Listeria monocytogenes via a cleavable linker (CD47-LLO). CD47-LLO promotes cancer cell phagocytosis by macrophages followed by LLO release and activation to form pores on phagolysosomal membranes that enhance antigen cross-presentation of tumor-derived peptides and activate cytosolic immune sensors. CD47-LLO treatment in vivo significantly inhibited the growth of both localized and metastatic breast and melanoma tumors and improved animal survival as a monotherapy or in combination with checkpoint blockade. Together, these results demonstrate that designing ATCs to promote immune recognition of tumor cells represents a promising therapeutic strategy for treating multiple cancers.

Keywords

Bacterial Toxins, Hemolysin Proteins, Animals, CD47 Antigen, Mice, Heat-Shock Proteins, Humans, Immunotherapy, Female, Phagocytosis, Cell Line, Tumor, Immunoconjugates, Macrophages, Neoplasms

Published Open-Access

yes

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