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CD47

CD47, also known as integrin-associated protein (IAP), is a ubiquitously expressed transmembrane glycoprotein belonging to the immunoglobulin superfamily, conserved across amniotes including mammals, reptiles, and birds. It is encoded by a gene located at chromosome 3q13.12 in humans and features an extracellular immunoglobulin variable-like (IgV) domain, a five-transmembrane-spanning region, and a short cytoplasmic tail that varies across isoforms due to alternative splicing, resulting in multiple proteoforms. CD47's primary function is to act as a ligand for signal regulatory protein alpha (SIRPα) on phagocytic cells such as macrophages, delivering a critical "don't eat me" signal that inhibits phagocytosis and maintains immune homeostasis by preventing the clearance of healthy self-cells. Beyond its role in phagocytosis regulation, CD47 participates in diverse cellular processes through interactions with thrombospondin-1 (TSP-1), (e.g., αvβ3 and αIIbβ3), and vascular endothelial growth factor receptor 2 (VEGFR2). These associations modulate , , , , and signaling pathways involving production, cyclic GMP (cGMP), and , with expression upregulated on hematopoietic, epithelial, endothelial, and s. In normal physiology, CD47 supports platelet activation, , blood flow regulation, and stem cell self-renewal, while post-translational modifications like N-glycosylation and pyroglutamylation further diversify its functional proteoforms. In disease contexts, CD47 is frequently overexpressed on tumor cells across various cancers, including , ovarian, breast, and , where it promotes immune evasion by enhancing the SIRPα-mediated inhibitory signal, correlating with poor prognosis and in many cases. Dysregulation also contributes to non-cancer conditions, such as , , autoimmune disorders, and aging-related muscle regeneration defects, where altered CD47 expression affects cell survival and tissue repair. Conversely, in some malignancies like , higher CD47 levels may bolster anti-tumor immunity. Therapeutically, CD47 has emerged as a promising target in , with blocking antibodies and fusion proteins designed to disrupt the CD47-SIRPα axis, thereby enhancing macrophage-mediated tumor and synergizing with , radiation, , and checkpoint inhibitors. As of November 2025, no CD47-targeted agents have been approved, but numerous clinical trials are evaluating CD47-targeted agents, though challenges including from red blood cell clearance and variable efficacy have led to program discontinuations, prompting refined strategies like bispecific antibodies and oncolytic viruses expressing anti-CD47 nanobodies; recent data from ALX Oncology's Phase 2 trials show promising responses in CD47-high expressing tumors, with over 80 agents in various stages of clinical development. Beyond , CD47 modulation holds potential for treating , ischemia-reperfusion injury, and by fine-tuning immune responses.

Structure

Primary Structure and Domains

CD47 is a transmembrane with an apparent molecular weight of approximately 50 kDa, belonging to the . The core protein consists of 293–323 in humans, yielding a theoretical mass of 31.88–35.22 kDa, while in mice it comprises 291–342 with a core mass of 31.71–37.3 kDa. The primary structure includes an N-terminal (residues 1–18, cleaved in the mature protein), an extracellular immunoglobulin variable-like (IgV) domain, a multiple membrane-spanning (MMS) domain featuring five transmembrane helices that confer a distinctive 5-TM topology among immune receptors, and a short C-terminal cytoplasmic tail varying from 4 to 36 across isoforms. The IgV domain, which supports ligand binding, is stabilized by two conserved bonds: one between Cys33 and Cys263 linking the IgV to the MMS domain, and another between Cys41 and Cys114 within the IgV domain itself. The overall topology and domain organization of CD47 have been elucidated by the of full-length human CD47 at 3.4 Å resolution. The CD47 gene resides on human 3q13.12, spanning 13 exons, and produces mRNA transcripts with alternative 3' (UTR) variants that modulate mRNA stability through interactions with RNA-binding proteins.

Isoforms and Post-Translational Modifications

CD47 undergoes alternative splicing primarily in the region encoding its C-terminal cytoplasmic tail, generating four isoforms that differ in tail length and composition (with a potential fifth isoform reported in limited contexts). In humans, the isoforms have total protein lengths of 293, 305, 312, and 323 amino acids, with tail lengths of approximately 4, 16, 20, and 36 amino acids, respectively; isoform 2, with a 16-amino-acid tail, is the most widely expressed. These variations arise from exon skipping in exons 8–13 of the CD47 gene and can influence intracellular signaling by altering motifs for protein interactions, such as binding sites for cytoplasmic partners like PLIC-1 in isoforms 2 and 4. In mice, alternative splicing produces up to 10 isoforms, incorporating additional variability in the extracellular domain (via exon 3 skipping) alongside tail variants analogous to those in humans, resulting in total lengths of 291–342 amino acids. Post-translational modifications (PTMs) further diversify CD47 into distinct proteoforms that affect its , localization, and function. N-linked occurs at multiple residues in the extracellular IgV , including potential sites at Asn23, Asn50, Asn73, Asn111, and Asn206; these modifications add approximately 15–20 to the core protein mass (from ~35 kDa to the observed 50 kDa), enhancing cell surface expression and . Additionally, the N-terminal residue is converted to pyroglutamate (pGlu) by the glutaminyl-peptide cyclotransferase-like (QPCTL) shortly after , a modification discovered in 2019 that stabilizes the and supports SIRPα binding; alterations to this pGlu can disrupt the interaction interface. Proteolytic cleavage by metalloproteases generates soluble CD47 (sCD47) fragments from the membrane-bound form, releasing extracellular portions into circulation that may modulate availability. In the cytoplasmic tail, at serine and residues, induced by activation via c-Src kinase, inhibits TRIM21-mediated polyubiquitination and lysosomal degradation, thereby increasing CD47 surface levels, as demonstrated in 2023 studies on tumor cells. At the mRNA level, alternative produces CD47 transcripts with short or long 3' untranslated regions (UTRs); in aged muscle cells, elevated U1 snRNA expression promotes the long 3' UTR isoform, leading to higher CD47 protein accumulation and impaired regenerative , as identified in 2022 research. This shift disrupts balanced expression, contributing to dysfunctional cellular states in aging tissues.

Molecular Interactions

With SIRP Family Proteins

CD47 interacts with high affinity with the (SIRPα), a receptor predominantly expressed on myeloid cells such as macrophages and dendritic cells, through the immunoglobulin variable-like (IgV) domain of CD47 and the N-terminal IgV domain of SIRPα. This interaction exhibits a (Kd) of approximately 1.2 μM, as determined by analysis of the extracellular domains. The binding interface is characterized by a convoluted involving the FG loop of CD47 inserting into a groove on SIRPα, facilitating between apposed cell surfaces. Upon ligation, the interaction triggers bidirectional signaling, primarily inhibitory on the SIRPα-expressing cell. Phosphorylation of the immunoreceptor tyrosine-based inhibition motifs (ITIMs) in SIRPα's cytoplasmic tail recruits the protein tyrosine phosphatases SHP-1 and SHP-2. These phosphatases dephosphorylate downstream targets, including components of the cytoskeleton regulatory pathways, thereby inhibiting actin polymerization and preventing phagocytic cup formation. This molecular cascade establishes CD47-SIRPα as a critical "don't eat me" signal in immune recognition. The CD47-SIRPα interaction is highly species-specific, with CD47 binding effectively to SIRPα but not to murine SIRPα, due to sequence divergences in the ligand-binding domains (approximately 34% identity between and SIRPα). This specificity complicates the translation of preclinical findings from models to applications, as CD47-expressing cells do not engage murine SIRPα . CD47 also binds SIRPγ, a related family member expressed on T cells and subsets of , though with lower affinity (Kd ≈ 23 μM). Unlike SIRPα, SIRPγ lacks ITIM motifs and does not mediate strong inhibitory signaling; instead, the interaction promotes T-cell to endothelial cells and costimulates under conditions, without inhibiting . Structural insights into the CD47-SIRPα complex were first provided by in 2008, resolving the interaction at 1.85–2.3 and revealing the IgV domain-mediated binding geometry. More recent structural studies in 2021 utilized cryo-electron microscopy (cryo-EM) at 9.8 for the full-length CD47 in complex with a blocking , alongside a 3.4 crystal structure, confirming the extracellular domain's orientation and its role in anchoring the interaction to the . A crystal structure of CD47 complexed with an engineered SIRPα variant (PDB: 7YGG) further elucidates the binding interface for therapeutic design. These structures highlight both cis interactions (CD47 and SIRPα on the same cell, modulating intrinsic signaling) and trans interactions (between opposing cells, driving primary inhibitory signals). Disruption of cis binding on macrophages enhances engulfment comparably to blocking trans interactions. The efficiency of CD47-SIRPα binding is regulated by a : pyroglutamate (pGlu) formation at the N-terminal residue (Q19) of CD47, catalyzed by glutaminyl-peptide cyclotransferase-like protein (QPCTL) in the Golgi apparatus. This modification, identified in through a haploid genetic screen, stabilizes the ligand-binding site and enhances affinity for SIRPα shortly after . QPCTL inhibition or reduces pGlu-CD47 levels, impairing the interaction and promoting macrophage-mediated of target cells.

With Thrombospondin-1

CD47 interacts with thrombospondin-1 (TSP-1) primarily through its extracellular immunoglobulin variable-like (IgV) , which serves as the key for the C-terminal of TSP-1. This interaction exhibits high affinity, with an apparent (Kd) of approximately 12 pM for full-length TSP-1 binding to CD47, enabling precise regulation of cellular responses. Specifically, the C-terminal strand of CD47's IgV engages the signature motif (containing VVM sequences) in TSP-1's C-terminal region, facilitating the formation of a ternary complex that incorporates such as αvβ3 or α4β1. This complex modulates cell-matrix adhesion by stabilizing engagement with extracellular matrix components, thereby influencing cellular spreading and in non-immune contexts. The TSP-1/CD47 signaling axis activates heterotrimeric G-protein-coupled pathways in vascular cells, leading to downstream effects on cyclic nucleotide levels. Binding of TSP-1 to CD47 inhibits nitric oxide synthase (NOS) activity, particularly endothelial NOS (eNOS), by suppressing NO production and preventing its stimulation of soluble guanylate cyclase (sGC). This results in reduced cGMP levels, while in certain vascular cell types, the pathway can elevate cAMP through modulation of phosphodiesterase activity, contributing to vasoconstriction and limited tissue perfusion. These G-protein-mediated signals are critical for TSP-1's role in restraining excessive vascular responses without involving immune surveillance mechanisms. TSP-1 engagement of CD47 promotes in endothelial cells and vascular cells by disrupting survival signaling and activating pro-apoptotic cascades. In endothelial cells, this interaction inhibits anti-apoptotic pathways like NO/cGMP, leading to caspase-independent and reduced vascular remodeling. Similarly, in cells, TSP-1/CD47 signaling induces under stress conditions, limiting and maintaining vascular . Structural insights into this process derive from molecular modeling studies of the TSP-1 C-terminal domain interacting with CD47, revealing conformational changes that expose binding interfaces and facilitate . Under hypoxic conditions, TSP-1 and CD47 expression are upregulated in endothelial and cells, enhancing their interaction to inhibit . This upregulation suppresses (VEGF) signaling via CD47-mediated disruption of VEGFR2 activation, thereby limiting endothelial proliferation and tube formation in low-oxygen environments. The resulting anti-angiogenic effect helps balance during tissue stress, preventing pathological vessel growth.

With Integrins

CD47 forms cis associations with several , including αvβ3, αIIbβ3, and α2β1, primarily through its extracellular IgV and contributions from its transmembrane region, which facilitate lateral interactions within the plasma membrane. These interactions enhance activation and clustering on the surface without CD47 acting as a direct for the , thereby modulating their conformational states and for extracellular matrix components. For instance, in platelets, CD47 binding to the C-terminal of thrombospondin-1 (TSP-1) physically modifies αIIbβ3, promoting its functional activation and supporting platelet aggregation. Similarly, in , CD47 augments α2β1-mediated adhesion and toward substrates. In the presence of TSP-1, CD47 participates in a ternary complex with such as αvβ3, where TSP-1 serves as a that stabilizes and initiates downstream signaling. This complex triggers activation of kinase (FAK) and family kinases, leading to events that promote cytoskeletal reorganization and cell spreading on substrates. The IgV domain of CD47 is critical for this ternary assembly, as it binds TSP-1 while the transmembrane and cytoplasmic tails of CD47 couple to signaling pathways, enhancing maturation without requiring cholesterol-dependent lipid rafts. Studies using CD47 knockout mice have demonstrated reduced integrin-mediated migration in platelets and leukocytes, underscoring the role of these associations in cellular motility. In CD47-deficient neutrophils, transendothelial migration across inflamed endothelium is impaired due to defective αvβ3 and β2 integrin functions, resulting in diminished leukocyte recruitment to sites of inflammation. Platelet aggregation and spreading on fibrinogen, which depend on αIIbβ3, are also compromised in the absence of CD47, highlighting its essential modulatory role. Structural evidence from fluorescence resonance energy transfer () imaging confirms the close proximity of CD47 and on cell surfaces, with distances typically less than 10 nm, consistent with direct cis interactions. In T cells, FRET analysis via (FLIM) revealed that CD47 associates laterally with β2 like LFA-1 (αLβ2), regulating their adhesive properties during immune cell trafficking. These nanoscale measurements support the mechanistic basis for CD47's enhancement of integrin clustering and mechanotransduction in various cell types.

Physiological Functions

Regulation of Phagocytosis and Immune Surveillance

CD47, originally identified in the early 1990s as integrin-associated protein (IAP), serves as a critical regulator of by acting as a marker of self on healthy cells. This transmembrane was found to co-purify with on leukocytes, highlighting its role in and signaling. The inhibitory function of CD47 in was definitively established in 2000 through studies on , which demonstrated accelerated clearance of red blood cells (RBCs) by splenic macrophages, indicating that CD47 normally suppresses unwarranted engulfment of self-cells. The CD47-SIRPα axis functions as the dominant "don't eat me" signal on healthy hematopoietic cells, preventing their by macrophages and dendritic cells. CD47 on target cells binds to signal regulatory protein α (SIRPα) on , triggering of SIRPα's immunoreceptor tyrosine-based inhibition motifs (ITIMs). This recruits the phosphatases SHP-1 and SHP-2, which dephosphorylate key cytoskeletal regulators, including components of the actin- network such as myosin IIA, thereby inhibiting phagocytic cup formation and downstream engulfment. The binding interface between CD47's IgV-like and the N-terminal IgV domain of SIRPα is essential for this inhibitory signaling. This mechanism ensures immune by balancing pro-phagocytic "eat me" signals, such as those from apoptotic cells, with inhibitory cues from viable self-cells. On erythrocytes, CD47 expression progressively decreases with cellular aging, serving as a physiological signal to mark senescent RBCs for clearance while maintaining protection for younger cells. This decline reduces the inhibitory CD47-SIRPα interaction, allowing macrophages to recognize and phagocytose aged RBCs in the . The process is counterbalanced by "eat me" signals like externalized on aging RBC membranes, which promote engulfment when CD47-mediated inhibition wanes. In CD47-deficient models, even young RBCs are rapidly cleared, underscoring CD47's dose-dependent role in erythrocyte . Beyond innate phagocytosis, CD47 contributes to adaptive immunity through its interaction with SIRPγ on T cells, promoting immune formation and T-cell activation to support steady-state self-. SIRPγ-CD47 binding enhances T-cell adhesion to antigen-presenting cells, facilitating stable conjugates and efficient without triggering inhibitory pathways. This interaction is particularly important in chronic or homeostatic immune contexts, where it helps maintain to self-antigens by modulating T-cell responses and preventing . Disruption of SIRPγ-CD47 impairs T-cell proliferation and production, highlighting its role in fine-tuning adaptive immune surveillance.

Cell Adhesion, Migration, and Proliferation

CD47 enhances -dependent cell adhesion and directed migration in various cell types, including leukocytes and fibroblasts, primarily through of focal adhesion kinase (FAK). In leukocytes, particularly T cells, CD47 is essential for regulating LFA-1 (αLβ2 ) adhesion to intercellular adhesion molecule-1 (), enabling efficient recruitment to endothelial cells during inflammation and immune responses. This process involves CD47's association with , which stabilizes s and promotes cytoskeletal reorganization necessary for cell motility. In fibroblasts, CD47 facilitates intercellular adhesion and motility by forming homophilic interactions that modulate function, independent of extracellular ligands, thereby supporting directed migration on extracellular matrices. CD47-mediated FAK further reinforces these effects by phosphorylating downstream targets that drive assembly and cell spreading, as observed in migratory epithelial models where CD47 loss impairs FAK signaling and motility. The role of CD47 in is context-dependent, often inhibitory in mature cells but supportive in populations. In endothelial cells, thrombospondin-1 (TSP-1) binding to CD47 disrupts receptor-2 (VEGFR2) association with αvβ3, inhibiting VEGFR2 and downstream signaling pathways that promote . This TSP-1/CD47 axis reduces endothelial by limiting Akt activation and production, thereby maintaining vascular . Elevated CD47 expression on hematopoietic s (HSCs) interacts with SIRPα to deliver a "don't eat me" signal, protecting HSCs from by macrophages and supporting their engraftment and maintenance in the niche. Additionally, CD47 signaling via thrombospondin-1 inhibits HSC self-renewal by suppressing transcription factors such as c-Myc. CD47 contributes to by promoting and supporting processes. In and other epithelial cells, CD47 regulates spreading and through actin cytoskeleton remodeling and dynamics, facilitating re-epithelialization at sites. CD47 associates with SHPS-1 (SIRPα) to modulate activity, preventing excessive inhibition of lamellipodia formation and enabling efficient epithelial sheet during repair. Genetic ablation of CD47 in mice impairs these processes, leading to delayed closure due to defective epithelial motility. Additionally, CD47 deficiency compromises platelet aggregation and ; CD47-null platelets exhibit reduced to vascular and subendothelial matrices, resulting in diminished generation and prolonged bleeding times. This underscores CD47's integral role in initial hemostatic plug formation via αIIbβ3 interactions. Beyond and , CD47 influences metabolic in pancreatic cells by modulating insulin . CD47 signaling tonically suppresses insulin release through deactivation of Cdc42, a Rho that coordinates ; pharmacological blockade of CD47 enhances glucose-stimulated insulin and improves function in islet models. This inhibitory effect helps fine-tune responsiveness to prevent , linking CD47 to systemic glucose .

Vascular and Metabolic Regulation

CD47 plays a critical role in vascular regulation by inhibiting through its interaction with thrombospondin-1 (TSP-1). This binding suppresses (NO) signaling in endothelial cells, which is essential for vascular development and tissue repair. Specifically, TSP-1 engagement of CD47 blocks the activation of soluble guanylate cyclase, reducing cyclic GMP levels and thereby limiting endothelial cell proliferation and migration in response to (VEGF). This mechanism ensures controlled vessel formation, preventing excessive that could disrupt normal vascular . In the context of , CD47 on vascular modulates responses by limiting transmigration across the . The CD47-SIRPα on endothelial surfaces inhibits leukocyte recruitment during inflammatory conditions, such as periodontitis, by downregulating adhesion molecules like and reducing IL-17-mediated signaling. Additionally, CD47 engagement suppresses release from endothelial cells, thereby attenuating excessive inflammatory cascades and maintaining vascular integrity during immune challenges. CD47 contributes to metabolic regulation, particularly in glucose , by protecting pancreatic from phagocytic clearance. Expressed on , CD47 binds SIRPα on macrophages, delivering a "don't eat me" signal that prevents unwarranted and preserves mass. This interaction stabilizes insulin secretion and supports glycemic control, as disruptions in the CD47-SIRPα axis lead to increased loss and impaired glucose tolerance. In bone metabolism, CD47 plays a role in , as its absence impairs osteoclast formation and results in an osteoporotic phenotype. SIRPα, expressed on , acts as an inhibitory receptor to regulate by limiting osteoclast function, such as actin ring assembly and podosome belt organization. This inhibitory pathway balances , ensuring that osteoclast-mediated resorption does not outpace osteoblast-driven formation, thereby maintaining skeletal .

Pathological Roles

In Cancer Progression and Immune Evasion

CD47 is upregulated in nearly all human cancers, serving as a critical mechanism for immune evasion by delivering a "don't eat me" signal that inhibits by macrophages through with SIRPα on phagocytic cells. This overexpression is observed in over 90% of cases, as well as in (AML), non-small cell (NSCLC), and numerous other solid and hematologic malignancies, where it correlates with advanced disease stages and poor overall survival. A of multiple cancer types confirms that elevated CD47 expression is significantly associated with reduced patient survival and increased tumor aggressiveness. In tumors, this pathway hijacks the normal regulation of to allow cancer cells to escape immune surveillance, thereby promoting tumor persistence and growth. Beyond immune evasion, CD47 contributes to tumor cell proliferation and survival through non-phagocytic mechanisms, including via CD47-SIRPα interactions on tumor cells themselves and association with to enhance and inhibit anoikis, the triggered by detachment from the . In and AML models, CD47 blockade reduces tumor by disrupting these survival signals, leading to decreased tumor burden. The CD47- complex, particularly with αvβ3, stabilizes kinase signaling, thereby preventing anoikis and supporting tumor cell viability during dissemination. CD47 also facilitates tumor migration and by promoting epithelial-mesenchymal transition () and invasive behavior through complexes involving thrombospondin-1 (TSP-1) and . In NSCLC, CD47 regulates pro-metastatic phenotypes through an ERK-dependent program. In , the CD47-TSP-1 association promotes cell and . These complexes further support metastatic dissemination, as evidenced by reduced extranodal in non-Hodgkin lymphoma models upon CD47 inhibition. In , high CD47 expression correlates with increased metastatic potential via TSP-1-mediated adhesion and immune escape. In cancer, shifts in CD47 proteoforms further amplify its oncogenic roles. Phosphorylation of CD47 at tyrosine 288, induced by EGFR activation via c-Src kinase, inhibits its ubiquitination and proteasomal degradation by TRIM21, leading to CD47 accumulation and sustained immune evasion in gliomas and other EGFR-driven tumors. Additionally, upregulated alternatively spliced CD47 isoforms are associated with stemness in pediatric AML, where they confer therapy resistance; splicing deregulation leading to these isoforms can be targeted by rebecsinib to disrupt leukemia stem cell maintenance.

In Non-Cancer Diseases

CD47 plays a significant role in the pathogenesis of , a major characterized by plaque formation in arterial walls. On , CD47 interacts with SIRPα on monocytes, facilitating their adhesion to the endothelium and subsequent transendothelial , which contributes to the recruitment of inflammatory cells into the vascular intima. This process is critical during the early stages of lesion development, as demonstrated in models where disruption of the CD47-SIRPα axis reduced monocyte adhesion under flow conditions. Furthermore, upregulated CD47 expression on macrophages within atherosclerotic plaques acts as a "don't eat me" signal, inhibiting of apoptotic cells and promoting accumulation, which exacerbates plaque progression and instability. Studies from the , including those using CD47-blocking antibodies in hyperlipidemic models, showed that targeting this pathway reduced lesion size by enhancing phagocytic clearance and limiting . In autoimmune and inflammatory conditions, dysregulated CD47-SIRPα signaling contributes to pathological immune responses. In , reduced CD47 expression on B cells leads to diminished inhibitory signaling through SIRPα on macrophages, resulting in enhanced of these cells and potentially amplifying autoimmune destruction of synovial tissues. This dysregulation correlates with disease activity and poorer response to B-cell depleting therapies like rituximab, highlighting CD47's role in modulating phagocytic thresholds during . Similarly, in , thrombospondin-1 (TSP-1) binding to CD47 on fibroblasts and inhibits signaling and , delaying granulation tissue formation and re-epithelialization. Transgenic models overexpressing TSP-1 demonstrated suppressed wound closure, underscoring how persistent TSP-1/CD47 activation impairs resolution in non-healing wounds, such as those in diabetic patients. CD47 is implicated in transplant-related pathologies, particularly in modulating graft rejection and ischemia-reperfusion injury. Overexpression of CD47 on donor graft cells delivers an inhibitory signal to macrophages via SIRPα, suppressing phagocytic attack and promoting tolerance, as evidenced by 2000s studies showing that CD47-deficient xenografts experienced accelerated rejection in models. This explains the protective effect of donor-specific transfusions, where CD47 engagement reduces acute rejection rates. In ischemia-reperfusion injury following transplantation, CD47 activation by TSP-1 suppresses production in vascular cells, leading to , endothelial , and exacerbated tissue damage upon flow restoration. Blocking CD47 in models of renal and cardiac ischemia-reperfusion restored NO-mediated vasodilation and improved graft viability, indicating its pathological contribution to post-transplant complications. During aging and neurodegeneration, alterations in CD47 expression on neurons influence microglial activity and contribute to cognitive decline. Reduced CD47 levels on senescent or stressed neurons diminish the "don't eat me" signal to , promoting excessive and clearance of viable cells, which accelerates neuronal loss in conditions like . Studies as of 2024 in amyloid-β models confirmed that neuronal CD47 overexpression protected against microglial engulfment and synaptic degeneration, preserving behavioral function. In parallel, CD47 signaling drives osteoclast hyperactivity in , where TSP-1/CD47 interactions enhance by promoting survival and differentiation. Studies in mouse models link CD47 activity to imbalanced remodeling and bone loss, with CD47 blockade mitigating osteoclastogenesis and preserving without affecting function.

Clinical Significance

Therapeutic Targeting

Therapeutic targeting of CD47 primarily focuses on disrupting its interaction with SIRPα to enhance macrophage-mediated phagocytosis of tumor cells, a strategy particularly promising in cancer immunotherapy. Anti-CD47 monoclonal antibodies (mAbs) represent the most advanced class of CD47-targeted agents. Magrolimab (Hu5F9-G4), a humanized IgG4 mAb, has been evaluated in phase III trials for untreated acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), often in combination with azacitidine; phase Ib data from 2023 reported complete remission (CR) rates of 33% and overall response rates (ORR) of 75% in higher-risk MDS patients, including those with TP53 mutations, though the 2025 ENHANCE-2 trial showed no overall survival benefit despite comparable response rates of approximately 30-40% in combination arms. However, following FDA clinical holds in 2024 and lack of survival benefit, Gilead paused further development of magrolimab in hematologic malignancies as of 2025. CC-90002, another humanized IgG4 anti-CD47 mAb, demonstrated antitumor activity in preclinical xenograft models of solid tumors, including triple-negative breast cancer, but its phase I trial (NCT02367196) was terminated in 2018 due to insufficient clinical activity. Similarly, AO-176, a non-depleting anti-CD47 mAb designed for preferential tumor cell binding, showed encouraging antitumor activity in a completed phase I/II trial (NCT03834948) for advanced solid tumors, with final phase 1 results presented in April 2025. SIRPα blockers and bispecific antibodies offer alternative approaches to potentiate while potentially reducing off-target effects. These agents, including bispecific constructs like CD47x, inhibit the CD47-SIRPα axis and synergize with PD-1/ blockade to enhance tumor clearance in preclinical models of various cancers. A key challenge is on-target due to red blood cell clearance, which can be mitigated by priming doses (e.g., 1 mg/kg) to saturate CD47 on normal cells before therapeutic dosing, as demonstrated with magrolimab and similar blockers. Inhibitors of pyroglutamyl peptidase-like (QPCTL), which catalyzes the N-terminal pyroglutamylation (pGlu) modification essential for -SIRPα binding, have emerged as a novel strategy. Preclinical compounds like DBPR22998, reported in 2024, significantly reduced CD47 surface binding and SIRPα interaction on tumor cells without affecting normal hematopoiesis, promoting in models. Thrombospondin-1 (TSP-1) mimetics target the CD47-TSP-1 pathway to address vascular diseases, where TSP-1/CD47 signaling promotes and . These agents, by modulating CD47 to inhibit TSP-1-mediated suppression, have shown potential in preclinical models of and to restore vascular function. Combination therapies amplify CD47 blockade efficacy. Pairing anti-CD47 agents with checkpoint inhibitors, such as rituximab (anti-CD20) in , yielded promising phase I/II results, including ORR up to 91% in ; ongoing 2025 trials with evorpacept (a CD47-SIRPα ) plus rituximab confirm safety and antitumor activity in relapsed/refractory . Rebecsinib, a splicing modulator, corrects aberrant in stem cells overexpressing CD47, resensitizing them to in preclinical pediatric AML models when combined with CD47 blockade. Beyond oncology, CD47 modulation is being explored in preclinical models for , ischemia-reperfusion injury, and as of 2025.

As a Biomarker and Diagnostic Tool

CD47 expression levels, both at the mRNA and protein level, serve as an adverse prognostic in multiple cancers. Elevated CD47 protein expression correlates with reduced overall survival in high-grade serous ovarian carcinoma. Similarly, a of solid tumors, including non-small cell (NSCLC), demonstrated that high CD47 expression is significantly associated with poor clinical outcomes, advanced tumor stages, and increased risk of , based on data from 4,019 patients across 20 studies. Soluble CD47 (sCD47) in has emerged as a non-invasive for monitoring hematological malignancies, particularly (AML). Levels of sCD47 are elevated in AML patients compared to healthy controls, with studies reporting up to 2-fold increases, facilitating disease detection and relapse monitoring through serial measurements. Additionally, proteoform profiling of CD47 using reveals isoform-specific variations linked to therapy resistance in cancers, where certain glycosylated proteoforms enhance immune evasion and predict poorer responses to checkpoint inhibitors. Beyond oncology, CD47 levels in non-cancer diseases offer diagnostic and prognostic value. Elevated serum CD47 levels predict in patients with , with a hazard ratio of 1.059 ( 1.010–1.110) over short-term follow-up. Conversely, reduced CD47 expression on aged cells, such as senescent red blood cells, acts as a for , signaling clearance by macrophages and aiding in the assessment of age-related tissue dysfunction. Emerging diagnostic approaches leverage CD47 for imaging and microenvironment analysis. Preclinical studies in 2025 have developed (PET) tracers using anti-CD47 nanobodies, enabling non-invasive visualization of CD47-overexpressing tumors in mouse models with high tumor-to-background ratios. Furthermore, low CD47 expression in the correlates with diminished infiltration and , predicting suboptimal immune responses and worse therapeutic outcomes in solid tumors like NSCLC.