CD47-Targeted Therapy in Cancer Immunotherapy: At a Crossroads of Promise and Challenge.

Introduction

The immune checkpoint molecule cluster of differentiation 47 (CD47), often described as the “don’t eat me” signal, has gained increasing attention for its role in promoting tumor immune evasion [ 1 , 2 ]. CD47 is broadly expressed on normal cells but is frequently upregulated in cancer, including hematologic malignancies and solid tumors, where it engages signal regulatory protein alpha (SIRPα) on macrophages and dendritic cells (DCs) [ 3 , 4 ]. This interaction transmits a potent anti-phagocytic signal that inhibits the clearance of tumor cells, allowing them to persist despite immunologic recognition [ 5 ].

Given its upstream role in immune regulation, CD47 has emerged as a promising therapeutic target with the potential to bridge innate and adaptive immunity [ 6 ]. This is especially relevant for immunologically “cold” tumors that lack sufficient T-cell infiltration and respond poorly to programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade [ 7 ].

Despite this strong rationale, clinical translation has been more complex than anticipated. However, clinical translation has been hampered by on-target/off-tumor toxicities (notably anemia and thrombocytopenia), suboptimal pharmacokinetics, and modest single-agent efficacy, which together have tempered initial enthusiasm [ 8 ]. To address these barriers, several next-generation strategies are under active investigation. SIRPα-targeted agents seek to bypass direct CD47 engagement and may reduce hematologic toxicity [ 9 ]. Bispecific antibodies pair CD47 blockade with tumor-restricted antigens (e.g., CD20, EpCAM) to improve selectivity, while conditionally active therapeutics are engineered to activate preferentially within the tumor microenvironment, thereby widening the therapeutic index and minimizing systemic exposure [ 10 ]. Together, these innovations represent a shift toward more clinically translatable approaches that address the limitations of first-generation CD47 inhibitors [ 11 ].

Over the past decade, this rationale has driven the development of multiple anti-CD47 therapeutics, including CD47 monoclonal antibodies (e.g., magrolimab, letaplimab, lemzoparlimab, ligufalimab (AK117), maplirpacept, and AUR103), SIRPα-Fc function protein (e.g., evorpacept (ALX148), IMM01, BYON4228), and bispecific antibodies (e.g., IBI322, TG1801, IMM0306), among others [ 12 ].

However, clinical experience with CD47 inhibition has been more complex than anticipated [ 13 – 15 ]. In July 2025, Pfizer terminated a Phase II trial of its investigational CD47-targeting fusion protein maplirpacept (PF-07901801) in combination with tafasitamab and lenalidomide for relapsed or refractory diffuse large B-cell lymphoma (DLBCL), citing an inability to recruit the planned number of subjects after enrolling only six patients since August 2023. The decision was explicitly stated to be unrelated to safety or efficacy concerns ( ClinicalTrials.gov Identifier: NCT05626322 ; last updated 29 June 2025). This follows a series of high-profile disappointments in the CD47 space, most notably Gilead’s complete discontinuation of magrolimab after multiple trial holds, including the termination of a Phase 3 study in higher-risk myelodysplastic syndrome (MDS) for futility (Gilead press release, 2023) and the termination of other ongoing MDS trials following cessation of magrolimab development ( ClinicalTrials.gov Identifier: NCT05835011 ; last updated 02 October 2024).

Together with other setbacks, these events highlight not only the biological and clinical complexities of CD47 blockade, including anemia from red blood cell clearance but also strategic and operational challenges in trial design, patient selection, and combination approaches. Collectively, these developments underscore the urgent need to re-evaluate CD47-targeted strategies. This commentary aims to contextualize recent clinical outcomes, dissect mechanistic insights, refine their clinical translation, and outline future directions for advancing CD47 blockade into durable, safe, and effective cancer immunotherapies.

Mechanistic Insights: Beyond the “Don’t Eat Me” Signal

The CD47-SIRPα interaction constitutes a multifaceted checkpoint at the interface of innate immunity [ 16 ]. CD47 is a transmembrane protein that binds the extracellular immunoglobulin variable (IgV) domain of SIRPα, an inhibitory receptor expressed predominantly on myeloid cells [ 17 ]. Upon ligand engagement, SIRPα’s intracellular immunoreceptor tyrosine-based inhibitory motifs (ITIMs) become phosphorylated, recruiting the SH2-domain containing phosphatases Src homology region 2 domain-containing phosphatase-1 (SHP-1) and Src homology region 2 domain-containing phosphatase-2 (SHP-2) [ 18 ]. These phosphatases dephosphorylate key effectors required for actin remodeling, effectively halting phagocytic-cup formation and target engulfment [ 19 ].

Importantly, this pathway not only suppresses macrophage phagocytosis but also limits antigen uptake and presentation by DCs [ 4 , 20 ]. Because antigen presentation is essential for initiating T-cell responses, CD47 functions as a pan-immune checkpoint, impairing both innate and adaptive immunity [ 2 , 6 ]. This provides strong rationale for therapeutic inhibition, particularly in tumors with poor T-cell infiltration or loss of major histocompatibility complex (MHC) expression.

Clinical Setbacks: Lessons from Anemia, Selectivity, and Limited Efficacy

Despite compelling biological rationale, CD47-targeted therapies have encountered significant clinical hurdles. A primary concern is on-target, off-tumor toxicity resulting from CD47 expression on red blood cells (RBCs) [ 21 , 22 ]. Antibodies with unmodified Fc domains can opsonize RBCs, causing anemia and dose-limiting toxicities that complicate safe and sustained treatment [ 23 ]. Beyond RBCs, additional on-target/off-tumor effects warrant consideration. These include thrombocytopenia due to platelet targeting, potential involvement of hematopoietic stem cells, and risks of cytokine release syndrome (CRS) or other immune-related adverse events in certain contexts, particularly in combination regimens [ 24 , 25 ].

In addition, monotherapy trials, particularly in solid tumors, have generally shown modest efficacy [ 26 , 27 ]. This limited activity likely reflects redundancy within the tumor microenvironment (TME), where alternative immune-evasion pathways compensate for CD47 blockade [ 1 ]. The absence of robust predictive biomarkers further obscures whether poor responses stem from intrinsic resistance or suboptimal patient selection [ 8 ].

These challenges do not negate CD47 as a therapeutic target; rather, they highlight the need for more refined approaches that integrate tumor context, rational combinations, and biomarker-driven precision [ 28 ]. To visualize these concepts, Fig. 1 depicts the dual roles of the CD47-SIRPα axis in tumor immune evasion and the restoration of antitumor immunity through combination strategies.

To complement this discussion, Table 1 summarizes key CD47-targeted agents, their modalities, sponsors, indications, and trial outcomes, highlighting the patterns of both progress and discontinuation across the clinical landscape. This structured overview underscores the translational challenges of CD47 blockade and sets the stage for mechanistic considerations illustrated in Fig. 1 .

Strategic Innovations in CD47-Based Therapy

Several approaches are being developed to overcome the limitations of first-generation CD47 inhibitors. Combination immunotherapy is among the most promising: co-blockade of CD47 with immune checkpoints such as PD-1, v-domain immunoglobulin suppressor of T cell activation (VISTA), or CD24 can synergistically restore phagocytosis, enhance antigen presentation, and reinvigorate exhausted T cells [ 29 – 31 ]. Such dual-targeting strategies are particularly appealing in tumors employing multiple, redundant layers of immune suppression [ 32 ].

Bispecific antibodies represent another strategy. By pairing CD47 blockade with tumor-specific targets (e.g., CD20 or EpCAM), these agents achieve selective activity on malignant cells while sparing RBCs and other healthy tissues. Early data suggest improved safety and specificity with this approach [ 33 , 34 ]. Likewise, nanoparticle-based delivery systems can localize CD47 inhibitors to the TME, enhancing the therapeutic index by reducing systemic exposure [ 35 , 36 ].

Targeting the receptor side of the axis is also gaining traction. SIRPα-directed agents including decoy receptors and fusion proteins, bypass the “red-cell sink” and directly activate myeloid cells, offering a potentially broader therapeutic window [ 37 – 39 ]. Several candidates are now advancing through early-phase clinical trials [ 40 , 41 ].

Rational integration with chemotherapy provides additional opportunities. Cytotoxic agents can upregulate CD47 in response to stress, sensitizing tumors to blockade [ 42 ]. Sequence-dependent combinations may be particularly relevant in diseases like ovarian cancer, where chemotherapy remains the frontline therapy [ 41 , 43 ].

Other innovative antibody formats are also being engineered. Fc-silencing and Fc-tuning reduce off-tumor effector functions; extended half-life variants and intratumoral delivery strategies provide spatial control of immune activation and may mitigate hematologic toxicity [ 44 , 45 ]. Novel constructs such as diphtheria toxin-based bivalently immunotoxins, expressed through yeast-based systems, have also demonstrated high specificity and potent efficacy against CD47 + cancers with minimized off-target binding [ 46 ].

Finally, dual-targeting strategies are emerging as a particularly promising avenue. Combining CD47 inhibition with pro-phagocytic “eat-me” signals, such as calreticulin (CALR), can amplify macrophage-mediated clearance of tumor cells. Similarly, pairing CD47 blockade with DNA damage response therapies, including poly (ADP-ribose) polymerase (PARP) inhibitors, has shown synergistic potential by promoting immunogenic stress responses and facilitating tumor cell recognition [ 47 , 48 ]. These approaches may be especially valuable in immunologically “cold” tumors lacking endogenous “eat-me” signals, thereby providing a rationale for rational dual-targeting combinations in future clinical development.

Future Perspectives: Contextual Precision in CD47 Blockade

The next generation of CD47-targeted and other precision immunotherapies will hinge on optimized drug design, rigorous patient selection, and context-specific application. A central challenge is identifying which morphologically, genetically, and metabolically heterogeneous tumors are functionally dependent on CD47-mediated immune evasion [ 3 , 49 ]. Advanced technologies such as single-cell profiling, spatial-transcriptomics, and special proteomics can delineate immune phenotypes and uncover predictive biomarkers [ 50 ].

Spatially resolved technologies, including multiplex immunohistochemistry (mIHC) and co-detection by indexing (CODEX), add crucial context by assessing not only macrophage abundance but also their polarization state (M1 vs. M2), proximity to tumor cells, and co-localization with T cells [ 51 ]. Tumors enriched with M2-like, SIRPα + macrophages at the invasive margin are more likely to benefit from CD47 blockade than those with sparse or M1-polarized macrophages [ 52 ]. Integrating these spatial metrics into biomarker development will refine patient stratification and guide rational therapeutic combinations [ 53 ].

Companion diagnostics incorporating CD47 expression levels, SIRPα isoforms, and myeloid signatures may further refine patient selection [ 54 , 55 ]. Such approaches could follow a stepwise process: baseline clinical evaluation to confirm diagnosis and associated symptoms, genetic risk stratification with mutation testing and identification of driver mutations, as well as immune transcriptomic profiling with comprehensive gene activity analysis, culminating in clustering by immune activity state (hyperactive, moderate, no active) [ 56 , 57 ].

The TME must also guide therapeutic choices. Macrophage-rich but T-cell-excluded tumors may benefit more from CD47 modulation than highly inflamed lesions dominated by lymphocytes [ 58 ]. Understanding each tumor’s immunologic “terrain” will be key to selecting effective combinations, whether with PD-1/PD-L1 antibodies, CD40 agonists, stimulator of interferon gene (STING) agonists, radiotherapy, or molecularly targeted drugs [ 59 , 60 ].

Clinical trial design should evolve accordingly. Adaptive frameworks incorporating real-time immune monitoring, pharmacodynamic biomarkers, and built-in combination arms can generate clearer efficacy signals and accelerate optimization [ 61 , 62 ]. Endpoints should extend beyond response rates to capture immune reprogramming within the TME [ 63 , 64 ]. In chronic lymphocytic leukemia (CLL), MDS, and multiple myeloma (MM), patient-oriented endpoints, including quality of life and patient-reported outcomes, will be essential to define the long-term value of CD47 blockade [ 65 ].

Conclusion

The CD47-SIRPα axis remains a compelling and versatile target in cancer immunotherapy. Recent clinical disappointments reflect the complexity of immune modulation rather than invalidation of the target itself. Moving forward, success will depend on strategic refinements of antibody engineering to minimize hematologic toxicity, biomarker-driven patient selection, and rational combinatorial regimens that exploit tumor context. The promise of CD47-targeted therapy lies not in questioning its relevance, but in applying it with precision: the right combinations, in the right patients, at the right time.

Acknowledgments

Not applicable.

Abbreviations

Acute myeloid leukemia

Calreticulin

Cluster of differentiation 47

Chronic lymphocytic leukemia

Co-detection by indexing

Cytokine release syndrome

Dendritic cell

Diffuse large B-cell lymphoma

Epithelial cell adhesion molecule

Granzyme B

Interferon-gamma

Immunoreceptor tyrosine-based inhibitory motif

Monoclonal antibody

Myelodysplastic syndrome

Multiplex immunohistochemistry

Major histocompatibility complex

Multiple myeloma

Natural killer

Poly (ADP-ribose) polymerase

Programmed cell death protein 1

Programmed death-ligand 1

perforin

Red blood cell

Src Homology region 2 domain-containing Phosphatase-1

Src Homology region 2 domain-containing Phosphatase-2

Signal regulatory protein alpha

Stimulator of interferon genes

Tumor microenvironment

Tumor necrosis factor-alpha

v-domain immunoglobulin suppressor of T cell activation

Funding Statement

The authors received no specific funding for this study.

Author Contributions

Xuejun Guo, Yilin Fu and Natalia Baran: Investigation, writing—original draft, review & editing. Wenxue Ma: Conceptualization, investigation, writing—original draft, visualization, review, editing, finalizing, and supervision. All authors reviewed the results and approved the final version of the manuscript.

Availability of Data and Materials

Not applicable.

Ethics Approval

Not applicable.

Conflicts of Interest

The authors declare no conflicts of interest to report regarding the present study.

References

1. Chen Q, Guo X, Ma W. Opportunities and challenges of CD47-targeted therapy in cancer immunotherapy. Oncol Res. 2023;32(1):49–60. doi: 10.32604/or.2023.042383;

2. Liu Y, Weng L, Wang Y, Zhang J, Wu Q, Zhao P, et al. Deciphering the role of CD47 in cancer immunotherapy. J Adv Res. 2024;63:129–58;

3. Ahvati H, Roudi R, Sobhani N, Safari F. CD47 as a potent target in cancer immunotherapy: a review. Biochim Biophys Acta Rev Cancer. 2025;1880(2):189294. doi: 10.1016/j.bbcan.2025.189294;

4. Zimarino C, Moody W, Davidson SE, Munir H, Shields JD. Disruption of CD47-SIRPalpha signaling restores inflammatory function in tumor-associated myeloid-derived suppressor cells. iScience. 2024;27(4):109546. doi: 10.1016/j.isci.2024.109546;

5. Zhou Y, Tang X, Du W, Shu C, Yan X, Ma N, et al. Deciphering the role of signal regulatory protein alpha in immunotherapy for solid tumors. Front Immunol. 2025;16:1612234. doi: 10.3389/fimmu.2025.1612234;

6. Hu A, Sun L, Lin H, Liao Y, Yang H, Mao Y. Harnessing innate immune pathways for therapeutic advancement in cancer. Signal Transduct Target Ther. 2024;9(1):68. doi: 10.1038/s41392-024-01765-9;

7. Wu B, Zhang B, Li B, Wu H, Jiang M. Cold and hot tumors: from molecular mechanisms to targeted therapy. Signal Transduct Target Ther. 2024;9(1):274. doi: 10.1038/s41392-024-01979-x;

8. Maute R, Xu J, Weissman IL. CD47-SIRPalpha-targeted therapeutics: status and prospects. Immunooncol Technol. 2022;13:100070. doi: 10.1016/j.iotech.2022.100070;

9. Haddad F, Daver N. Targeting CD47/SIRPalpha in acute myeloid leukemia and myelodysplastic syndrome: preclinical and clinical developments of magrolimab. J Immunother Precis Oncol. 2021;4(2):67–71. doi: 10.36401/jipo-21-x2;

10. Zhang B, Li W, Fan D, Tian W, Zhou J, Ji Z, et al. Advances in the study of CD47-based bispecific antibody in cancer immunotherapy. Immunology. 2022;167(1):15–27. doi: 10.1111/imm.13498;

11. Chen Y, Shi W, Shi J, Lu J. Progress of CD47 immune checkpoint blockade agents in anticancer therapy: a hematotoxic perspective. J Cancer Res Clin Oncol. 2022;148(1):1–14. doi: 10.1007/s00432-021-03815-z;

12. Xu Y, Jiang P, Xu Z, Ye H. Opportunities and challenges for anti-CD47 antibodies in hematological malignancies. Front Immunol. 2024;15:1348852. doi: 10.3389/fimmu.2024.1348852;

13. Yang H, Xun Y, You H. The landscape overview of CD47-based immunotherapy for hematological malignancies. Biomark Res. 2023;11(1):15. doi: 10.1186/s40364-023-00456-x;

14. Sun T, Nguyen B, Chen S, Natkunam Y, Padda S, van de Rijn M, et al. Brief report: high levels of CD47 expression in thymic epithelial tumors. JTO Clin Res Rep. 2023;4(4):100498. doi: 10.1016/j.jtocrr.2023.100498;

15. Al-Sudani H, Ni Y, Jones P, Karakilic H, Cui L, Johnson LDS, et al. Targeting CD47-SIRPa axis shows potent preclinical anti-tumor activity as monotherapy and synergizes with PARP inhibition. NPJ Precis Oncol. 2023;7(1):69. doi: 10.1038/s41698-023-00418-4;

16. Fenalti G, Villanueva N, Griffith M, Pagarigan B, Lakkaraju SK, Huang RY, et al. Structure of the human marker of self 5-transmembrane receptor CD47. Nat Commun. 2021;12(1):5218. doi: 10.1038/s41467-021-25475-w;

17. Xu L, Wang X, Zhang T, Meng X, Zhao W, Pi C, et al. Expression of a mutant CD47 protects against phagocytosis without inducing cell death or inhibiting angiogenesis. Cell Rep Med. 2024;5(3):101450. doi: 10.1016/j.xcrm.2024.101450;

18. Zhang B, Zou Y, Tang Q, Yuan Z, Jiang K, Zhang Z, et al. SIRPalpha modulates microglial efferocytosis and neuroinflammation following experimental subarachnoid hemorrhage via the SHP1/STAT6 axis. J Neuroinflammation. 2025;22(1):88. doi: 10.1186/s12974-025-03414-6;

19. Le T, Ferling I, Qiu L, Nabaile C, Assuncao L, Roskelley CD, et al. Redistribution of the glycocalyx exposes phagocytic determinants on apoptotic cells. Dev Cell. 2024;59(7):853–68.e7. doi: 10.1016/j.devcel.2024.01.020;

20. Zhao H, Song S, Ma J, Yan Z, Xie H, Feng Y, et al. CD47 as a promising therapeutic target in oncology. Front Immunol. 2022;13:757480. doi: 10.3389/fimmu.2022.757480;

21. Osorio JC, Smith P, Knorr DA, Ravetch JV. The antitumor activities of anti-CD47 antibodies require Fc-FcgammaR interactions. Cancer Cell. 2023;41(12):2051–65. e6. doi: 10.1101/2023.06.29.547082;

22. Reischer A, Leutbecher A, Hiller B, Perini E, White K, Hernandez-Caceres A, et al. Targeted CD47 checkpoint blockade using a mesothelin-directed antibody construct for enhanced solid tumor-specific immunotherapy. Cancer Immunol Immunother. 2025;74(7):214. doi: 10.1007/s00262-025-04032-0;

23. Bauer-Smith H, Sudol ASL, Beers SA, Crispin M. Serum immunoglobulin and the threshold of Fc receptor-mediated immune activation. Biochim Biophys Acta Gen Subj. 2023;1867(11):130448. doi: 10.1016/j.bbagen.2023.130448;

24. Ansell S, Maris M, Lesokhin A, Chen R, Flinn IW, Sawas A, et al. Phase I study of the CD47 blocker TTI-621 in patients with relapsed or refractory hematologic malignancies. Clin Cancer Res. 2021;27(8):2190–9. doi: 10.1158/1078-0432.ccr-20-3706;

25. Sun J, Chen Y, Lubben B, Adebayo O, Muz B, Azab AK. CD47-targeting antibodies as a novel therapeutic strategy in hematologic malignancies. Leuk Res Rep. 2021;16(6230):100268. doi: 10.1016/j.lrr.2021.100268;

26. Chen C, Lu F, Huang H, Pan Y. Translating CD47-targeted therapy in gastrointestinal cancers: insights from preclinical to clinical studies. iScience. 2024;27(12):111478. doi: 10.1016/j.isci.2024.111478;

27. Yamada-Hunter SA, Theruvath J, McIntosh BJ, Freitas KA, Lin F, Radosevich MT, et al. Engineered CD47 protects T cells for enhanced antitumour immunity. Nature. 2024;630(8016):457–65. doi: 10.1038/s41586-024-07443-8;

28. Morchon-Araujo D, Catani G, Mirallas O, Pretelli G, Sanchez-Perez V, Vieito M, et al. Emerging immunotherapy targets in early drug development. Int J Mol Sci. 2025;26(11):5394. doi: 10.3390/ijms26115394;

29. Li Y, Jia W, Zhu M, Hu X, Ya Z, Liu Y, et al. Focused acoustic vortex-activated dual-stimuli nanoplatform synergizes with checkpoint blockade to enhance macrophage phagocytosis and antitumor immunity. ACS Nano. 2025;19(30):27957–76. doi: 10.1021/acsnano.5c10591;

30. Christo S, McDonald K, Burn T, Kurd N, Stanfield J, Kaneda M, et al. Dual CD47 and PD-L1 blockade elicits anti-tumor immunity by intratumoral CD8(+) T cells. Clin Transl Immunol. 2024;13(11):e70014. doi: 10.1002/cti2.70014;

31. Martins T, Kaymak D, Tatari N, Gerster F, Hogan S, Ritz MF, et al. Enhancing anti-EGFRvIII CAR T cell therapy against glioblastoma with a paracrine SIRPgamma-derived CD47 blocker. Nat Commun. 2024;15(1):9718. doi: 10.1101/2023.08.31.555122.

32. Zhuang T, Zhang C, Strati P. SOHO state of the art updates and next questions | novel immunotherapy combinations for the treatment of indolent B-cell lymphoma. Clin Lymphoma Myeloma Leuk. 2025;25(7):455–64. doi: 10.1016/j.clml.2025.01.021;

33. Shan K, Musleh Ud Din S, Dalal S, Gonzalez T, Dalal M, Ferraro P, et al. Bispecific antibodies in solid tumors: advances and challenges. Int J Mol Sci. 2025;26(12):5838. doi: 10.3390/ijms26125838;

34. Ma L, Zhu M, Gai J, Li G, Chang Q, Qiao P, et al. Preclinical development of a novel CD47 nanobody with less toxicity and enhanced anti-cancer therapeutic potential. J Nanobiotechnol. 2020;18(1):12. doi: 10.1186/s12951-020-0571-2;

35. Sabir S, Thani A, Abbas Q. Nanotechnology in cancer treatment: revolutionizing strategies against drug resistance. Front Bioeng Biotechnol. 2025;13:1548588. doi: 10.3389/fbioe.2025.1548588;

36. Papp T, Zeng J, Shahnawaz H, Akyianu A, Breda L, Yadegari A, et al. CD47 peptide-cloaked lipid nanoparticles promote cell-specific mRNA delivery. Mol Ther. 2025;33(7):3195–208. doi: 10.1016/j.ymthe.2025.03.018;

37. Andrejeva G, Capoccia B, Hiebsch R, Donio MJ, Darwech I, Puro RJ, et al. Novel SIRPalpha antibodies that induce single-agent phagocytosis of tumor cells while preserving T cells. J Immunol. 2021;206(4):712–21. doi: 10.4049/jimmunol.2001019;

38. Qu T, Li B, Wang Y. Targeting CD47/SIRPalpha as a therapeutic strategy, where we are and where we are headed. Biomark Res. 2022;10(1):20. doi: 10.1186/s40364-022-00373-5;

39. Isenberg J, Montero E. Tolerating CD47. Clin Transl Med. 2024;14(2):e1584;

40. van Helden MJ, Zwarthoff SA, Arends RJ, Reinieren-Beeren IMJ, Parade M, Driessen-Engels L, et al. BYON4228 is a pan-allelic antagonistic SIRPalpha antibody that potentiates destruction of antibody-opsonized tumor cells and lacks binding to SIRPgamma on T cells. J Immunother Cancer. 2023;11(4):e006567. doi: 10.1158/1538-7445.am2022-5589.

41. Lakhani N, Stewart D, Richardson D, Dockery L, Van Le L, Call J, et al. First-in-human phase I trial of the bispecific CD47 inhibitor and CD40 agonist Fc-fusion protein, SL-172154 in patients with platinum-resistant ovarian cancer. J Immunother Cancer. 2025;13(1):e010565. doi: 10.1136/jitc-2024-010565;

42. Lau A, Khavkine Binstock S, Thu K. CD47: the next frontier in immune checkpoint blockade for non-small cell lung cancer. Cancers. 2023;15(21):5229. doi: 10.3390/cancers15215229;

43. Zhao L, Wang X, Liu H, Lang J. Chemotherapy-induced increase in CD47 expression in epithelial ovarian cancer. Gland Surg. 2024;13(10):1770–84. doi: 10.21037/gs-24-400;

44. Yin N, Li X, Zhang X, Xue S, Cao Y, Niedermann G, et al. Development of pharmacological immunoregulatory anti-cancer therapeutics: current mechanistic studies and clinical opportunities. Signal Transduct Target Ther. 2024;9(1):126. doi: 10.1038/s41392-024-01826-z;

45. Li H, Zhou Q, Cao N, Hu C, Wang J, He Y, et al. Nanobodies and their derivatives: pioneering the future of cancer immunotherapy. Cell Commun Signal. 2025;23(1):271;

46. Ma J, Wang Z, Mintzlaff D, Zhang H, Ramakrishna R, Davila E, et al. Bivalent CD47 immunotoxin for targeted therapy of T-cell acute lymphoblastic leukemia. Blood. 2025;145(5):508–19. doi: 10.1182/blood.2024025277;

47. Zhang Y, Luo J, Zhang J, Miao W, Wu J, Huang H, et al. Nanoparticle-enabled dual modulation of phagocytic signals to improve macrophage-mediated cancer immunotherapy. Small. 2020;16(46):e2004240. doi: 10.1002/smll.202004240;

48. Liu Y, Xue R, Duan X, Shang X, Wang M, Wang F, et al. PARP inhibition synergizes with CD47 blockade to promote phagocytosis by tumor-associated macrophages in homologous recombination-proficient tumors. Life Sci. 2023;326(4):121790. doi: 10.1016/j.lfs.2023.121790;

49. Bian H, Shen Y, Zhou Y, Nagle D, Guan Y, Zhang W, et al. CD47: beyond an immune checkpoint in cancer treatment. Biochim Biophys Acta Rev Cancer. 2022;1877(5):188771. doi: 10.1016/j.bbcan.2022.188771;

50. Jin Y, Wu Y, Reuben A, Zhu L, Gay CM, Wu Q, et al. Single-cell and spatial proteo-transcriptomic profiling reveals immune infiltration heterogeneity associated with neuroendocrine features in small cell lung cancer. Cell Discov. 2024;10(1):93. doi: 10.1038/s41421-024-00755-z;

51. Matusiak M, Hickey J, van ID, Lu G, Kidzinski L, Zhu S, et al. Spatially segregated macrophage populations predict distinct outcomes in colon cancer. Cancer Discov. 2024;14(8):1418–39. doi: 10.1158/2159-8290.cd-23-1300;

52. Liu M, Bertolazzi G, Sridhar S, Lee R, Jaynes P, Mulder K, et al. Spatially-resolved transcriptomics reveal macrophage heterogeneity and prognostic significance in diffuse large B-cell lymphoma. Nat Commun. 2024;15(1):2113. doi: 10.1038/s41467-024-46220-z;

53. Khanduri I, Maki H, Verma A, Katkhuda R, Anandappa G, Pandurengan R, et al. New insights into macrophage polarization and its prognostic role in patients with colorectal cancer liver metastasis. BJC Rep. 2024;2(1):37. doi: 10.21203/rs.3.rs-3439308/v1;

54. Li Q, Geng S, Luo H, Wang W, Mo YQ, Luo Q, et al. Signaling pathways involved in colorectal cancer: pathogenesis and targeted therapy. Signal Transduct Target Ther. 2024;9(1):266. doi: 10.1038/s41392-024-01953-7;

55. Singh S, Dey D, Barik D, Mohapatra I, Kim S, Sharma M, et al. Glioblastoma at the crossroads: current understanding and future therapeutic horizons. Signal Transduct Target Ther. 2025;10(1):213. doi: 10.1038/s41392-025-02299-4;

56. Che Z, Wang W, Zhang L, Lin Z. Therapeutic strategies targeting CD47-SIRPalpha signaling pathway in gastrointestinal cancers treatment. J Pharm Anal. 2025;15(1):101099. doi: 10.1016/j.jpha.2024.101099;

57. Yu W, Ye Z, Shi J, Deng W, Chen J, Lu JJ. Dual blockade of GSTK1 and CD47 improves macrophage-mediated phagocytosis on cancer cells. Biochem Pharmacol. 2025;236(10400):116898. doi: 10.1016/j.bcp.2025.116898;

58. Saeed A. Tumor-associated macrophages: polarization, immunoregulation, and immunotherapy. Cells. 2025;14(10):741. doi: 10.3390/cells14100741;

59. Yang S, Ta YN, Chen Y. Nanotechnology-enhanced immunotherapies for pancreatic ductal adenocarcinoma: challenges and opportunities. Drug Deliv Transl Res. 2025;379(25):2395. doi: 10.1007/s13346-025-01908-7;

60. Li T, Zhang W, Niu M, Wu Y, Deng X, Zhou J. STING agonist inflames the cervical cancer immune microenvironment and overcomes anti-PD-1 therapy resistance. Front Immunol. 2024;15:1342647. doi: 10.3389/fimmu.2024.1342647;

61. Marron T, Luke J, Hoffner B, Perlmutter J, Szczepanek C, Anagnostou V, et al. A SITC vision: adapting clinical trials to accelerate drug development in cancer immunotherapy. J Immunother Cancer. 2025;13(3):e010760. doi: 10.1136/jitc-2024-010760;

62. Luke J, Bever K, Hodi F, Taube J, Massey A, Yao D, et al. Rationale and feasibility of a rapid integral biomarker program that informs immune-oncology clinical trials: the ADVISE trial. J Immunother Cancer. 2025;13(5):e011170. doi: 10.1136/jitc-2024-011170;

63. Imani S, Farghadani R, Roozitalab G, Maghsoudloo M, Emadi M, Moradi A, et al. Reprogramming the breast tumor immune microenvironment: cold-to-hot transition for enhanced immunotherapy. J Exp Clin Cancer Res. 2025;44(1):131. doi: 10.1186/s13046-025-03394-8;

64. Wang Q, Ma W. Revisiting TAM polarization: beyond M1- and M2-type TAM toward clinical precision in macrophage-targeted therapy. Exp Mol Pathol. 2025;143:104982. doi: 10.1016/j.yexmp.2025.104982;

65. Patel K, Ivanov A, Jocelyn T, Hantel A, Garcia J, Abel G. Patient-reported outcomes in phase 3 clinical trials for blood cancers: a systematic review. JAMA Netw Open. 2024;7(6):e2414425. doi: 10.1001/jamanetworkopen.2024.14425;

Associated Data

Data Availability Statement

Not applicable.