Biomedicine

Abstract

Cluster of Differentiation 47 (CD47), also known as integrin-associated protein (IAP), is a ubiquitously expressed transmembrane protein that functions as a key innate immune checkpoint by delivering a “don’t-eat-me” signal to prevent macrophage-mediated phagocytosis of healthy cells. This inhibitory mechanism is mediated through the interaction of CD47 on target cells with signal regulatory protein-α (SIRPα) present on macrophages and dendritic cells. Tumor cells frequently exploit this pathway by overexpressing CD47, allowing them to evade immune surveillance, enhance survival, and promote malignant progression. Consequently, therapeutic targeting of the CD47/SIRPα axis has emerged as a promising strategy in cancer immunotherapy. Blocking CD47-SIRPα interactions using monoclonal antibodies, fusion proteins, or engineered SIRPα variants enhances macrophage-mediated phagocytosis, improves antigen presentation, and stimulates robust innate and adaptive antitumor immune responses. Preclinical and early clinical studies have demonstrated encouraging activity of these agents across various cancer types, either as monotherapy or in combination with immune checkpoint inhibitors, chemotherapy, or antibody-drug conjugates. However, clinical translation remains challenging because CD47 is broadly expressed on normal hematopoietic cells, leading to potential toxicities such as anemia, thrombocytopenia, and leukopenia. Thus, achieving tumor-selective targeting while minimizing off-target effects is critical for safe and effective therapy. Ongoing research focuses on improving antibody specificity, optimizing dosing regimens, and developing next-generation CD47/SIRPα-targeted agents with superior safety profiles. This review highlights the immunoregulatory role of CD47 in tumor immune escape, summarizes recent therapeutic advancements, and underscores the importance of refining CD47-based strategies to enhance clinical outcomes and support their integration into modern cancer immunotherapy.