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LLO-CD47 (also referred to as CD47-LLO) is a first-in-class antibody-toxin conjugate (ATC) designed for cancer immunotherapy. It consists of a monoclonal antibody targeting the myeloid checkpoint CD47 conjugated to listeriolysin O (LLO), a pore-forming protein derived from Listeria monocytogenes, via a cleavable linker. Developed by researchers at the University of Texas MD Anderson Cancer Center, LLO-CD47 blocks the CD47-SIRPα 'don't eat me' signaling axis to promote macrophage-mediated phagocytosis of tumor cells. Upon internalization into the acidic phagolysosomes of antigen-presenting cells (APCs), the linker is cleaved, releasing LLO. LLO then forms pores in the phagolysosomal membrane, allowing tumor-derived DNA and antigenic peptides to escape into the cytosol. This cytosolic release activates the cGAS-STING pathway, leading to pro-inflammatory M1 macrophage polarization, enhanced antigen cross-presentation, and robust CD8+ T-cell-mediated antitumor immune responses. LLO-CD47 has demonstrated preclinical efficacy in inhibiting the growth and metastasis of breast cancer and melanoma.
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