The FEBS journalJul 14, 2025

Improving immune cell cancer clearance by blocking the SIRPα/CD47 signal and targeting the MUC1 protein

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Feb 28, 2026

Abstract

SIRPα knockout (KO) THP-1 cells displayed enhanced of bioparticles and leukemic cell lines compared to wild-type (WT) counterparts.

Disruption of the SIRPα/CD47 interaction may facilitate immune activation by promoting phagocytosis.
SIRPα KO THP-1 cells retained their monocyte and macrophage characteristics.
Enhanced phagocytosis was observed in SIRPα KO THP-1 cells for leukemic cell lines but not for breast cancer cell lines.
The introduction of a CAR targeting the tMUC1 antigen improved phagocytic activity against the breast cancer line MCF-7.
These findings suggest potential therapeutic applications of SIRPα KO macrophages in treating hematologic malignancies.

Simplified

Signal regulatory protein alpha (SIRPα) is an essential immune checkpoint, predominantly expressed on myeloid cells, that binds to CD47. This interaction, termed the 'don't eat me' signal, contributes to immune suppression. Consequently, disruption of the emerges as a promising strategy to intervene in the 'don't eat me' signal, thereby initiating phagocytic activation. Various preclinical and clinical studies employed SIRPα/CD47-targeting molecules to disrupt the SIRPα/CD47 axis to promote cancer . However, concerns regarding their limited efficacy and side effects pose a challenge to applying this approach to cancer therapy. Here, we investigated the role of the SIRPα/CD47 axis in phagocytosis by performing clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-mediated SIRPA gene disruption in the monocytic cell line THP-1. The SIRPα knockout (KO) THP-1 cells were comprehensively characterized for their phenotype and functions, including differentiation into M0 macrophages, polarization into M1 or M2 macrophages, and phagocytosis of bioparticles and cancer cells, and compared to their wild-type (WT) counterparts. The SIRPα KO THP-1 cells retained their monocyte and macrophage characteristics. Remarkably, they exhibited enhanced phagocytosis of bioparticles and leukemic cell lines but not breast cancer cell lines. The introduction of a chimeric antigen receptor (CAR) targeting tumor-associated mucin1 antigen (tMUC1-CAR) further enhanced their phagocytic activity against the breast cancer cell line, MCF-7, which expresses high levels of MUC1. Our findings highlight the therapeutic potential of SIRPα KO macrophages in cancer immunotherapy, particularly for hematologic malignancies. However, a combination with CAR was necessary to enhance the phagocytic activity against solid cancer models.

Key numbers

94%

Increase in Phagocytic Activity

Indicates the percentage of indel mutations in SIRPα KO THP-1 cells.

3 of 3

Enhanced of Leukemic Cells

Leukemic cell lines tested showed increased by SIRPα KO THP-1 cells.

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Improving immune cell cancer clearance by blocking the SIRPα/CD47 signal and targeting the MUC1 protein

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