Translating CD47-targeted therapy in gastrointestinal cancers: Insights from preclinical to clinical studies

Abstract

This review presents a thorough investigation of the role of CD47 in gastrointestinal cancers. We performed a comprehensive, in-depth review of over 100 preclinical and clinical studies focused on inhibiting CD47. The research highlights the potential of targeted CD47 to enhance existing treatments by boosting the immune response to cancer cells. Considering the essential need to balance the toxicity and efficacy of CD47 inhibition, our review emphasizes the need to optimize CD47 inhibitors. We also demonstrate the necessity of combining CD47 antibodies with conventional chemotherapy, radiotherapy, or other targeted therapies to enhance treatment effectiveness. Finally, we propose the integration of CD47-targeted therapies into treatment plans as a promising approach to reshape the therapeutic landscape of gastrointestinal cancers. Continued research in this field holds great potential for improving the outcomes of gastrointestinal cancer patients and overcoming the challenges associated with this formidable spectrum of diseases.

Keywords: Health sciences; Immunology; Internal medicine; Medical specialty; Medicine; Natural sciences; Oncology.

Graphical abstract

Figure 1

CD47-SIRPα interaction in immune regulation When CD47 on tumor cells binds to SIRPα on macrophages, it triggers the phosphorylation of immunoreceptor tyrosine-based inhibitory motifs (ITIMs), recruiting Src homology region 2 domain-containing phosphatases (SHP-1 and SHP-2), which inactivate myosin IIA, thereby blocking phagocytosis (“Don’t eat me” signal). In dendritic cells, this interaction inhibits maturation and cytokine production, preventing CD8⁺ and CD4⁺ T cell activation, allowing tumor cells to evade immune destruction.

Figure 2

Timeline of CD47/SIRPα clinical trials and key developments

Figure 3

Mechanisms of action for CD47/SIRPα blockade in tumor cells Anti-CD47 monoclonal antibodies induce additional immune responses, such as antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity, via Fc receptor activation on natural killer cells and complement proteins like C1qsAnti-SIRPα monoclonal antibodies and SIRPα-Fc fusion proteins also enhance macrophage-mediated phagocytosis by preventing CD47 from interacting with SIRPα on immune cells. Moreover, CD47 blockade enhances dendritic cell activation, promoting T cell cross-priming and boosting CD8⁺ T cell-mediated tumor cell killing. Finally, CD47 inhibition can directly induce tumor cell apoptosis through non-immune pathways.