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Novel immunotherapy for gastric cancer: targeting the CD47–SIRPα axis

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Abstract

Gastric cancer (GC) represents a significant global health challenge, with limited therapeutic options and poor outcomes. Although cancer immunotherapies targeting adaptive immune checkpoints, such as programmed death-1, have transformed the landscape of cancer treatment, their efficacy in GC is limited to a small subset of patients, emphasizing the unmet clinical need for novel therapeutic strategies. Cluster of differentiation 47 (CD47), referred to as the “don’t eat me” signal, enables tumor cells to evade phagocytosis by binding to signal regulatory protein alpha (SIRPα) on myeloid cells, such as macrophages and dendritic cells. This interaction inhibits the innate immune response, thereby facilitating tumor progression and resistance to existing therapies. Targeting the CD47–SIRPα axis may be a potent strategy to enhance macrophage-mediated phagocytosis and activate antitumor adaptive immunity. However, on-target off-tumor toxicity and heterogeneity of the immunosuppressive tumor microenvironment remain substantial challenges, which pose significant barriers to effective treatment. Recently, the impressive results of a phase II ASPEN-06 trial provide proof-of-concept, indicating CD47–SIRPα blockade as a promising approach for patients with GC. This review comprehensively elucidates the CD47–SIRPα signaling pathway, highlighting its role in tumor immune evasion and the current advancements in therapeutic strategies targeting this axis. Drawing on insights from recent clinical trials and preclinical studies, we discuss potential approaches for developing effective CD47–SIRPα-targeted therapies in GC.

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Data availability

No datasets were generated or analyzed during the current study.

Abbreviations

DC:

Endritic cell

TCR:

T cell receptor

MHC:

Major histocompatibility complex

References

  1. Sung, H., Ferlay, J., Siegel, R. L., et al. (2021). Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer J Clin, 71, 209–249.

    Google Scholar 

  2. Balakrishnan, M., George, R., Sharma, A., & Graham, D. Y. (2017). Changing trends in stomach cancer throughout the world. Current Gastroenterology Rep, 19, 36.

    Article  Google Scholar 

  3. The National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology, Gastric Cancer. https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf. 2024;version 5.

  4. Shitara, K., Fleitas, T., Kawakami, H., et al. (2024). Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with gastric cancer. ESMO Open., 9, 102226.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Japanese Gastric Cancer Treatment Guidelines. (2021). 6th edition. Gastric Cancer, 2023(26), 1–25.

    Google Scholar 

  6. Wagner, A. D., Syn, N. L., Moehler, M., et al. (2017). Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev, 8, Cd004064.

  7. Ooki, A., Shinozaki, E., & Yamaguchi, K. (2021). Immunotherapy in colorectal cancer: Current and future strategies. J Anus Rectum Colon., 5, 11–24.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Ooki, A., Osumi, H., Chin, K., Watanabe, M., & Yamaguchi, K. (2023). Potent molecular-targeted therapies for advanced esophageal squamous cell carcinoma. Ther Adv Med Oncol., 15, 17588359221138376.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Ooki, A., Osumi, H., Yoshino, K., & Yamaguchi, K. (2024). Yamaguchi K. Potent therapeutic strategy in gastric cancer with microsatellite instability-high and/or deficient mismatch repair. Gastric Cancer.

  10. Ooki, A., & Yamaguchi, K. (2022). The dawn of precision medicine in diffuse-type gastric cancer. Ther Adv Med Oncol., 14, 17588359221083048.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Kang, Y. K., Boku, N., Satoh, T., et al. (2017). Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet, 390, 2461–2471.

    Article  PubMed  Google Scholar 

  12. Waldman, A. D., Fritz, J. M., & Lenardo, M. J. (2020). A guide to cancer immunotherapy: From T cell basic science to clinical practice. Nature Reviews Immunology, 20, 651–668.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Keren, L., Bosse, M., Marquez, D., et al. (2018). A structured tumor-immune microenvironment in triple negative breast cancer revealed by multiplexed ion beam imaging. Cell, 174, 1373-1387.e1319.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Kim, I. S., Gao, Y., Welte, T., et al. (2019). Immuno-subtyping of breast cancer reveals distinct myeloid cell profiles and immunotherapy resistance mechanisms. Nature Cell Biology, 21, 1113–1126.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Pittet, M. J., Michielin, O., & Migliorini, D. (2022). Clinical relevance of tumour-associated macrophages. Nature Reviews. Clinical Oncology, 19, 402–421.

    Article  PubMed  Google Scholar 

  16. Mantovani, A., Allavena, P., Marchesi, F., & Garlanda, C. (2022). Macrophages as tools and targets in cancer therapy. Nature Reviews. Drug Discovery, 21, 799–820.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Willingham, S. B., Volkmer, J. P., Gentles, A. J., et al. (2012). The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc Natl Acad Sci U S A., 109, 6662–6667.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Matlung, H. L., Szilagyi, K., Barclay, N. A., & van den Berg, T. K. (2017). The CD47-SIRPα signaling axis as an innate immune checkpoint in cancer. Immunological Reviews, 276, 145–164.

    Article  PubMed  Google Scholar 

  19. Komori, S., Saito, Y., Nishimura, T., et al. (2023). CD47 promotes peripheral T cell survival by preventing dendritic cell-mediated T cell necroptosis. Proc Natl Acad Sci U S A., 120, e2304943120.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Feng, M., Jiang, W., Kim, B. Y. S., Zhang, C. C., Fu, Y. X., & Weissman, I. L. (2019). Phagocytosis checkpoints as new targets for cancer immunotherapy. Nature Reviews Cancer, 19, 568–586.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Liu, Z., Chen, H., Ta, N., et al. (2023). Anti-CD47 antibody enhances the efficacy of chemotherapy in patients with gastric cancer liver metastasis. Journal of Cancer, 14, 350–359.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Tseng, D., Volkmer, J. P., Willingham, S. B., et al. (2013). Anti-CD47 antibody-mediated phagocytosis of cancer by macrophages primes an effective antitumor T-cell response. Proc Natl Acad Sci U S A., 110, 11103–11108.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Sockolosky, J. T., Dougan, M., Ingram, J. R., et al. (2016). Durable antitumor responses to CD47 blockade require adaptive immune stimulation. Proc Natl Acad Sci U S A., 113, E2646-2654.

    Article  PubMed  PubMed Central  Google Scholar 

  24. von Roemeling, C. A., Wang, Y., Qie, Y., et al. (2020). Therapeutic modulation of phagocytosis in glioblastoma can activate both innate and adaptive antitumour immunity. Nature Communications, 11, 1508.

    Article  Google Scholar 

  25. Shitara, K. W. Z., Tabernero, J., et al. (2025). Final analysis of the randomized phase 2 part of the ASPEN-06 study: A phase 2/3 study of evorpacept (ALX148), a CD47 myeloid checkpoint inhibitor, in patients with HER2-overexpressing gastric/gastroesophageal cancer (GC). Journal of Clinical Oncology, 43, 332.

    Article  Google Scholar 

  26. Iwasaki, A., & Medzhitov, R. (2010). Regulation of adaptive immunity by the innate immune system. Science, 327, 291–295.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Jutras, I., & Desjardins, M. (2005). Phagocytosis: At the crossroads of innate and adaptive immunity. Annual Review of Cell and Developmental Biology, 21, 511–527.

    Article  PubMed  Google Scholar 

  28. Wynn, T. A., Chawla, A., & Pollard, J. W. (2013). Macrophage biology in development, homeostasis and disease. Nature, 496, 445–455.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Liu, X., Pu, Y., Cron, K., et al. (2015). CD47 blockade triggers T cell-mediated destruction of immunogenic tumors. Nature Medicine, 21, 1209–1215.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Chao, M. P., Jaiswal, S., Weissman-Tsukamoto, R., et al. (2010). Calreticulin is the dominant pro-phagocytic signal on multiple human cancers and is counterbalanced by CD47. Sci Transl Med, 2, 63ra94.

  31. Barclay, A. N., & Van den Berg, T. K. (2014). The interaction between signal regulatory protein alpha (SIRPα) and CD47: Structure, function, and therapeutic target. Annual Review of Immunology, 32, 25–50.

    Article  PubMed  Google Scholar 

  32. Tsai, R. K., & Discher, D. E. (2008). Inhibition of “self” engulfment through deactivation of myosin-II at the phagocytic synapse between human cells. Journal of Cell Biology, 180, 989–1003.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Kharitonenkov, A., Chen, Z., Sures, I., Wang, H., Schilling, J., & Ullrich, A. (1997). A family of proteins that inhibit signalling through tyrosine kinase receptors. Nature, 386, 181–186.

    Article  PubMed  Google Scholar 

  34. Li, Y., Zhou, H., Liu, P., et al. (2023). SHP2 deneddylation mediates tumor immunosuppression in colon cancer via the CD47/SIRPα axis. J Clin Invest, 133.

  35. Seiffert, M., Cant, C., Chen, Z., et al. (1999). Human signal-regulatory protein is expressed on normal, but not on subsets of leukemic myeloid cells and mediates cellular adhesion involving its counterreceptor CD47. Blood, 94, 3633–3643.

    Article  PubMed  Google Scholar 

  36. Murata, T., Ohnishi, H., Okazawa, H., et al. (2006). CD47 promotes neuronal development through Src- and FRG/Vav2-mediated activation of Rac and Cdc42. Journal of Neuroscience, 26, 12397–12407.

    Article  PubMed  Google Scholar 

  37. Adams, S., van der Laan, L. J., Vernon-Wilson, E., et al. (1998). Signal-regulatory protein is selectively expressed by myeloid and neuronal cells. The Journal of Immunology, 161, 1853–1859.

    Article  PubMed  Google Scholar 

  38. Hedrick, C. C., & Malanchi, I. (2022). Neutrophils in cancer: Heterogeneous and multifaceted. Nature Reviews Immunology, 22, 173–187.

    Article  PubMed  Google Scholar 

  39. Kong, X. N., Yan, H. X., Chen, L., et al. (2007). LPS-induced down-regulation of signal regulatory protein alpha contributes to innate immune activation in macrophages. Journal of Experimental Medicine, 204, 2719–2731.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Dong, L. W., Kong, X. N., Yan, H. X., et al. (2008). Signal regulatory protein alpha negatively regulates both TLR3 and cytoplasmic pathways in type I interferon induction. Molecular Immunology, 45, 3025–3035.

    Article  PubMed  Google Scholar 

  41. Zen, K., Guo, Y., Bian, Z., et al. (2013). Inflammation-induced proteolytic processing of the SIRPα cytoplasmic ITIM in neutrophils propagates a proinflammatory state. Nature Communications, 4, 2436.

    Article  PubMed  Google Scholar 

  42. Londino, J. D., Gulick, D., Isenberg, J. S., & Mallampalli, R. K. (2015). Cleavage of signal regulatory protein α (SIRPα) enhances inflammatory signaling. Journal of Biological Chemistry, 290, 31113–31125.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Uhlén, M., Fagerberg, L., Hallström, B. M., et al. (2015). Proteomics. Tissue-based map of the human proteome. Science, 347, 1260419.

  44. Myers, L. M., Tal, M. C., Torrez Dulgeroff, L. B., et al. (2019). A functional subset of CD8(+) T cells during chronic exhaustion is defined by SIRPα expression. Nature Communications, 10, 794.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Barclay, A. N., & Brown, M. H. (2006). The SIRP family of receptors and immune regulation. Nature Reviews Immunology, 6, 457–464.

    Article  PubMed  Google Scholar 

  46. Brooke, G., Holbrook, J. D., Brown, M. H., & Barclay, A. N. (2004). Human lymphocytes interact directly with CD47 through a novel member of the signal regulatory protein (SIRP) family. The Journal of Immunology, 173, 2562–2570.

    Article  PubMed  Google Scholar 

  47. Oldenborg, P. A., Zheleznyak, A., Fang, Y. F., Lagenaur, C. F., Gresham, H. D., & Lindberg, F. P. (2000). Role of CD47 as a marker of self on red blood cells. Science, 288, 2051–2054.

    Article  PubMed  Google Scholar 

  48. Olsson, M., Bruhns, P., Frazier, W. A., Ravetch, J. V., & Oldenborg, P. A. (2005). Platelet homeostasis is regulated by platelet expression of CD47 under normal conditions and in passive immune thrombocytopenia. Blood, 105, 3577–3582.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Casey, S. C., Tong, L., Li, Y., et al. (2016). MYC regulates the antitumor immune response through CD47 and PD-L1. Science, 352, 227–231.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Zhang, H., Lu, H., Xiang, L., et al. (2015). HIF-1 regulates CD47 expression in breast cancer cells to promote evasion of phagocytosis and maintenance of cancer stem cells. Proc Natl Acad Sci U S A., 112, E6215-6223.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Berkovits, B. D., & Mayr, C. (2015). Alternative 3′ UTRs act as scaffolds to regulate membrane protein localization. Nature, 522, 363–367.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Suzuki, S., Yokobori, T., Tanaka, N., et al. (2012). CD47 expression regulated by the miR-133a tumor suppressor is a novel prognostic marker in esophageal squamous cell carcinoma. Oncology Reports, 28, 465–472.

    Article  PubMed  Google Scholar 

  53. Yang, S. Y., Choi, S. A., Lee, J. Y., et al. (2015). miR-192 suppresses leptomeningeal dissemination of medulloblastoma by modulating cell proliferation and anchoring through the regulation of DHFR, integrins, and CD47. Oncotarget, 6, 43712–43730.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Kang, G., Jiao, Y., Pan, P., et al. (2023). α5-nAChR/STAT3/CD47 axis contributed to nicotine-related lung adenocarcinoma progression and immune escape. Carcinogenesis, 44, 773–784.

    Article  PubMed  Google Scholar 

  55. Arai, H., Gandhi, N., Battaglin, F., et al. (2023). The role of gene expression of CD47 in colorectal cancer (CRC). Journal of Clinical Oncology., 41, 240–240.

    Article  Google Scholar 

  56. Liu, Y., Chang, Y., He, X., et al. (2020). CD47 enhances cell viability and migration ability but inhibits apoptosis in endometrial carcinoma cells via the PI3K/Akt/mTOR signaling pathway. Frontiers in Oncology, 10, 1525.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Jiang, N., Xie, B., Xiao, W., et al. (2022). Fatty acid oxidation fuels glioblastoma radioresistance with CD47-mediated immune evasion. Nature Communications, 13, 1511.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Kaur, S., & Roberts, D. D. (2011). CD47 applies the brakes to angiogenesis via vascular endothelial growth factor receptor-2. Cell Cycle, 10, 10–12.

    Article  PubMed  Google Scholar 

  59. Gordon, S. R., Maute, R. L., Dulken, B. W., et al. (2017). PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature, 545, 495–499.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Noy, R., & Pollard, J. W. (2014). Tumor-associated macrophages: From mechanisms to therapy. Immunity, 41, 49–61.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Zhang, M., Hutter, G., Kahn, S. A., et al. (2016). Anti-CD47 Treatment stimulates phagocytosis of glioblastoma by M1 and M2 polarized macrophages and promotes M1 polarized macrophages in vivo. PLoS ONE, 11, e0153550.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Tian, L., Xu, B., Teng, K. Y., et al. (2022). Targeting Fc receptor-mediated effects and the “Don’t Eat Me” signal with an oncolytic virus expressing an anti-CD47 antibody to treat metastatic ovarian cancer. Clinical Cancer Research, 28, 201–214.

    Article  PubMed  Google Scholar 

  63. Shi, M., Gu, Y., Jin, K., et al. (2021). CD47 expression in gastric cancer clinical correlates and association with macrophage infiltration. Cancer Immunology, Immunotherapy, 70, 1831–1840.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Zhang, K., Xu, Y., Chang, X., et al. (2024). Co-targeting CD47 and VEGF elicited potent anti-tumor effects in gastric cancer. Cancer Immunology, Immunotherapy, 73, 75.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Gao, L., Chen, K., Gao, Q., Wang, X., Sun, J., & Yang, Y. G. (2017). CD47 deficiency in tumor stroma promotes tumor progression by enhancing angiogenesis. Oncotarget, 8, 22406–22413.

    Article  PubMed  Google Scholar 

  66. de Vries, H. E., Hendriks, J. J., Honing, H., et al. (2002). Signal-regulatory protein alpha-CD47 interactions are required for the transmigration of monocytes across cerebral endothelium. The Journal of Immunology, 168, 5832–5839.

    Article  PubMed  Google Scholar 

  67. Pengam, S., Durand, J., Usal, C., et al. (2019). SIRPα/CD47 axis controls the maintenance of transplant tolerance sustained by myeloid-derived suppressor cells. American Journal of Transplantation, 19, 3263–3275.

    Article  PubMed  Google Scholar 

  68. Nath, P. R., Gangaplara, A., Pal-Nath, D., et al. (2018). CD47 expression in natural killer cells regulates homeostasis and modulates immune response to lymphocytic choriomeningitis virus. Frontiers in Immunology, 9, 2985.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Nath, P. R., Pal-Nath, D., Mandal, A., Cam, M. C., Schwartz, A. L., & Roberts, D. D. (2019). Natural killer cell recruitment and activation are regulated by CD47 expression in the tumor microenvironment. Cancer Immunology Research, 7, 1547–1561.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Ma, D., Liu, S., Lal, B., et al. (2019). Extracellular matrix protein tenascin C increases phagocytosis mediated by CD47 loss of function in glioblastoma. Cancer Research, 79, 2697–2708.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Sudo, T., Takahashi, Y., Sawada, G., Uchi, R., Mimori, K., & Akagi, Y. (2017). Significance of CD47 expression in gastric cancer. Oncology Letters, 14, 801–809.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Hoffmann, W. (2012). Stem cells, self-renewal and cancer of the gastric epithelium. Current Medicinal Chemistry, 19, 5975–5983.

    Article  PubMed  Google Scholar 

  73. Gupta, A., Taslim, C., Tullius, B. P., & Cripe, T. P. (2020). Therapeutic modulation of the CD47-SIRPα axis in the pediatric tumor microenvironment: Working up an appetite. Cancer Drug Resist., 3, 550–562.

    PubMed  PubMed Central  Google Scholar 

  74. Chen, S., Zhan, S., Ding, S., et al. (2023). B7–H3 and CD47 co-expression in gastric cancer is a predictor of poor prognosis and potential targets for future dual-targeting immunotherapy. Journal of Cancer Research and Clinical Oncology, 149, 16609–16621.

    Article  PubMed  Google Scholar 

  75. Yoshida, K., Tsujimoto, H., Matsumura, K., et al. (2015). CD47 is an adverse prognostic factor and a therapeutic target in gastric cancer. Cancer Medicine, 4, 1322–1333.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Zhou, Y., Zeng, J., Zhou, W., Wu, K., Tian, Z., & Shen, W. (2022). Prognostic significance of CKS2 and CD47 expression in patients with gastric cancer who underwent radical gastrectomy. Scandinavian Journal of Immunology, 96, e13198.

    Article  PubMed  Google Scholar 

  77. Fan, Y., Song, S., Li, Y., et al. (2023). Galectin-3 cooperates with CD47 to suppress phagocytosis and T-cell immunity in gastric cancer peritoneal metastases. Cancer Research, 83, 3726–3738.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Arai, H., Gandhi, N., Battaglin, F., et al. (2024). Role of CD47 gene expression in colorectal cancer: A comprehensive molecular profiling study. J Immunother Cancer, 12.

  79. Duan, Y., Li, S., Huang, B., et al. (2023). CD47-targeted immunotherapy unleashes antitumour immunity in Epstein-Barr virus-associated gastric cancer. Clinical Immunology, 247, 109238.

    Article  PubMed  Google Scholar 

  80. Abe, H., Saito, R., Ichimura, T., et al. (2018). CD47 expression in Epstein-Barr virus-associated gastric carcinoma: Coexistence with tumor immunity lowering the ratio of CD8(+)/Foxp3(+) T cells. Virchows Archiv, 472, 643–651.

    Article  PubMed  Google Scholar 

  81. Network, C. G. A. R. (2014). Comprehensive molecular characterization of gastric adenocarcinoma. Nature, 513, 202–209.

    Article  Google Scholar 

  82. Zhao, Q., Cai, Q., Yu, S., et al. (2021). Combinatorial analysis of AT-rich interaction domain 1A and CD47 in gastric cancer patients reveals markers of prognosis. Front Cell Dev Biol., 9, 745120.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Wang, K., Kan, J., Yuen, S. T., et al. (2011). Exome sequencing identifies frequent mutation of ARID1A in molecular subtypes of gastric cancer. Nature Genetics, 43, 1219–1223.

    Article  PubMed  Google Scholar 

  84. Cristescu, R., Lee, J., Nebozhyn, M., et al. (2015). Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nature Medicine, 21, 449–456.

    Article  PubMed  Google Scholar 

  85. Dieci, M. V., Arnedos, M., Andre, F., & Soria, J. C. (2013). Fibroblast growth factor receptor inhibitors as a cancer treatment: From a biologic rationale to medical perspectives. Cancer Discovery, 3, 264–279.

    Article  PubMed  Google Scholar 

  86. Ooki, A., & Yamaguchi, K. (2021). The beginning of the era of precision medicine for gastric cancer with fibroblast growth factor receptor 2 aberration. Gastric Cancer, 24, 1169–1183.

    Article  PubMed  Google Scholar 

  87. Albano, F., Severini, F. L., Calice, G., Zoppoli, P., Falco, G., & Notarangelo, T. (2025). The role of the tumor microenvironment and inflammatory pathways in driving drug resistance in gastric cancer: A systematic review and meta-analysis. Biochimica et Biophysica Acta, Molecular Basis of Disease, 1871, 167821.

    Article  PubMed  Google Scholar 

  88. Yang, Y., Meng, W. J., & Wang, Z. Q. (2021). Cancer stem cells and the tumor microenvironment in gastric cancer. Frontiers in Oncology, 11, 803974.

    Article  PubMed  Google Scholar 

  89. Yun, H., Dong, F., Wei, X., et al. (2025). Role and value of the tumor microenvironment in the progression and treatment resistance of gastric cancer (Review). Oncol Rep, 53.

  90. Oya, Y., Hayakawa, Y., & Koike, K. (2020). Tumor microenvironment in gastric cancers. Cancer Science, 111, 2696–2707.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Li, S., Cong, X., Gao, H., et al. (2019). Tumor-associated neutrophils induce EMT by IL-17a to promote migration and invasion in gastric cancer cells. Journal of Experimental & Clinical Cancer Research, 38, 6.

    Article  Google Scholar 

  92. Zhu, Q., Zhang, X., Zhang, L., et al. (2014). The IL-6-STAT3 axis mediates a reciprocal crosstalk between cancer-derived mesenchymal stem cells and neutrophils to synergistically prompt gastric cancer progression. Cell Death & Disease, 5, e1295.

    Article  Google Scholar 

  93. Liu, T., Guo, S., Ji, Y., & Zhu, W. (2023). Role of cancer-educated mesenchymal stromal cells on tumor progression. Biomedicine & Pharmacotherapy, 166, 115405.

    Article  Google Scholar 

  94. Shan, Z. G., Chen, J., Liu, J. S., et al. (2021). Activated neutrophils polarize protumorigenic interleukin-17A-producing T helper subsets through TNF-α-B7-H2-dependent pathway in human gastric cancer. Clinical and Translational Medicine, 11, e484.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Tsutsumi, C., Ohuchida, K., Katayama, N., et al. (2024). Tumor-infiltrating monocytic myeloid-derived suppressor cells contribute to the development of an immunosuppressive tumor microenvironment in gastric cancer. Gastric Cancer, 27, 248–262.

    Article  PubMed  Google Scholar 

  96. Zhou, X., Fang, D., Liu, H., et al. (2022). PMN-MDSCs accumulation induced by CXCL1 promotes CD8(+) T cells exhaustion in gastric cancer. Cancer Letters, 532, 215598.

    Article  PubMed  Google Scholar 

  97. Sun, H., Wang, X., Wang, X., Xu, M., & Sheng, W. (2022). The role of cancer-associated fibroblasts in tumorigenesis of gastric cancer. Cell Death & Disease, 13, 874.

    Article  Google Scholar 

  98. Qu, Y., Wang, X., Bai, S., et al. (2022). The effects of TNF-α/TNFR2 in regulatory T cells on the microenvironment and progression of gastric cancer. International Journal of Cancer, 150, 1373–1391.

    Article  PubMed  Google Scholar 

  99. Qin, Y., Wang, F., Ni, H., et al. (2021). Cancer-associated fibroblasts in gastric cancer affect malignant progression via the CXCL12-CXCR4 axis. Journal of Cancer, 12, 3011–3023.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Abe, A., Nagatsuma, A. K., Higuchi, Y., Nakamura, Y., Yanagihara, K., & Ochiai, A. (2017). Site-specific fibroblasts regulate site-specific inflammatory niche formation in gastric cancer. Gastric Cancer, 20, 92–103.

    Article  PubMed  Google Scholar 

  101. Zhang, Y., Cong, X., Li, Z., & Xue, Y. (2020). Estrogen facilitates gastric cancer cell proliferation and invasion through promoting the secretion of interleukin-6 by cancer-associated fibroblasts. International Immunopharmacology, 78, 105937.

    Article  PubMed  Google Scholar 

  102. Kwon, M., An, M., Klempner, S. J., et al. (2021). Determinants of response and intrinsic resistance to PD-1 blockade in microsatellite instability-high gastric cancer. Cancer Discovery, 11, 2168–2185.

    Article  PubMed  Google Scholar 

  103. Merlo, A., Turrini, R., Dolcetti, R., et al. (2010). The interplay between Epstein-Barr virus and the immune system: A rationale for adoptive cell therapy of EBV-related disorders. Haematologica, 95, 1769–1777.

    Article  PubMed  PubMed Central  Google Scholar 

  104. Fuyuhiro, Y., Yashiro, M., Noda, S., et al. (2011). Upregulation of cancer-associated myofibroblasts by TGF-β from scirrhous gastric carcinoma cells. British Journal of Cancer, 105, 996–1001.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Hasegawa, T., Yashiro, M., Nishii, T., et al. (2014). Cancer-associated fibroblasts might sustain the stemness of scirrhous gastric cancer cells via transforming growth factor-β signaling. International Journal of Cancer, 134, 1785–1795.

    Article  PubMed  Google Scholar 

  106. Mateo, V., Lagneaux, L., Bron, D., et al. (1999). CD47 ligation induces caspase-independent cell death in chronic lymphocytic leukemia. Nature Medicine, 5, 1277–1284.

    Article  PubMed  Google Scholar 

  107. Chao, M. P., Alizadeh, A. A., Tang, C., et al. (2010). Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma. Cell, 142, 699–713.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Jaiswal, S., Jamieson, C. H., Pang, W. W., et al. (2009). CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell, 138, 271–285.

    Article  PubMed  PubMed Central  Google Scholar 

  109. Majeti, R., Chao, M. P., Alizadeh, A. A., et al. (2009). CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell, 138, 286–299.

    Article  PubMed  PubMed Central  Google Scholar 

  110. Weiskopf, K., Jahchan, N. S., Schnorr, P. J., et al. (2016). CD47-blocking immunotherapies stimulate macrophage-mediated destruction of small-cell lung cancer. The Journal of Clinical Investigation, 126, 2610–2620.

    Article  PubMed  PubMed Central  Google Scholar 

  111. Liu, Q., Wen, W., Tang, L., et al. (2016). Inhibition of SIRPα in dendritic cells potentiates potent antitumor immunity. Oncoimmunology., 5, e1183850.

    Article  PubMed  PubMed Central  Google Scholar 

  112. Yu, J., Li, S., Chen, D., et al. (2022). SIRPα-Fc fusion protein IMM01 exhibits dual anti-tumor activities by targeting CD47/SIRPα signal pathway via blocking the “don’t eat me” signal and activating the “eat me” signal. Journal of Hematology & Oncology, 15, 167.

    Article  Google Scholar 

  113. Soto-Pantoja, D. R., Terabe, M., Ghosh, A., et al. (2014). CD47 in the tumor microenvironment limits cooperation between antitumor T-cell immunity and radiotherapy. Cancer Research, 74, 6771–6783.

    Article  PubMed  PubMed Central  Google Scholar 

  114. Veillette, A., & Chen, J. (2018). SIRPα-CD47 Immune checkpoint blockade in anticancer therapy. Trends in Immunology, 39, 173–184.

    Article  PubMed  Google Scholar 

  115. Xu, M. M., Pu, Y., Han, D., et al. (2017). Dendritic cells but not macrophages sense tumor mitochondrial DNA for cross-priming through signal regulatory protein α signaling. Immunity, 47, 363-373.e365.

    Article  PubMed  PubMed Central  Google Scholar 

  116. Nimmerjahn, F., & Ravetch, J. V. (2008). Fcgamma receptors as regulators of immune responses. Nature Reviews Immunology, 8, 34–47.

    Article  PubMed  Google Scholar 

  117. Gül, N., & van Egmond, M. (2015). Antibody-dependent phagocytosis of tumor cells by macrophages: A potent effector mechanism of monoclonal antibody therapy of cancer. Cancer Research, 75, 5008–5013.

    Article  PubMed  Google Scholar 

  118. Xu, B., Tian, L., Chen, J., et al. (2021). An oncolytic virus expressing a full-length antibody enhances antitumor innate immune response to glioblastoma. Nature Communications, 12, 5908.

    Article  PubMed  PubMed Central  Google Scholar 

  119. Sallman, D. A., Al Malki, M. M., Asch, A. S., et al. (2023). Magrolimab in combination with azacitidine in patients with higher-risk myelodysplastic syndromes: Final results of a phase Ib study. Journal of Clinical Oncology, 41, 2815–2826.

    Article  PubMed  PubMed Central  Google Scholar 

  120. Daver, N. G., Vyas, P., Kambhampati, S., et al. (2023). Tolerability and efficacy of the anticluster of differentiation 47 antibody magrolimab combined with azacitidine in patients with previously untreated AML: Phase Ib results. Journal of Clinical Oncology, 41, 4893–4904.

    Article  PubMed  PubMed Central  Google Scholar 

  121. Daver, N., Konopleva, M., Maiti, A., et al. (2021). Phase I/II study of azacitidine (AZA) with venetoclax (VEN) and magrolimab (Magro) in patients (pts) with newly diagnosed older/unfit or high-risk acute myeloid leukemia (AML) and relapsed/refractory (R/R) AML. Blood, 138, 371.

    Article  Google Scholar 

  122. Sikic, B. I., Lakhani, N., Patnaik, A., et al. (2019). First-in-human, first-in-class phase I trial of the anti-CD47 antibody Hu5F9-G4 in patients with advanced cancers. Journal of Clinical Oncology, 37, 946–953.

    Article  PubMed  PubMed Central  Google Scholar 

  123. Patnaik, A., Spreafico, A., Paterson, A. M., et al. (2020). Results of a first-in-human phase I study of SRF231, a fully human, high-affinity anti-CD47 antibody. Journal of Clinical Oncology., 38, 3064–3064.

    Article  Google Scholar 

  124. Lim, H. Y., Ahn, J. S., Park, J. O., et al. (2024). Updated safety, efficacy, pharmacokinetics, and biomarkers from the phase 1 study of IMC-002, a novel anti-CD47 monoclonal antibody, in patients with advanced solid tumors. Journal of Clinical Oncology., 42, 2642–2642.

    Article  Google Scholar 

  125. Zhang, Q., Liu, A., Shi, J., et al. (2023). A first-in-human study of MIL95, an anti-CD47 monoclonal antibody (mAb), in patients with advanced solid tumors and lymphomas. Journal of Clinical Oncology., 41, e14513–e14513.

    Article  Google Scholar 

  126. Weiskopf, K., Ring, A. M., Ho, C. C., et al. (2013). Engineered SIRPα variants as immunotherapeutic adjuvants to anticancer antibodies. Science, 341, 88–91.

    Article  PubMed  Google Scholar 

  127. Advani, R., Flinn, I., Popplewell, L., et al. (2018). CD47 blockade by Hu5F9-G4 and rituximab in non-Hodgkin’s lymphoma. New England Journal of Medicine, 379, 1711–1721.

    Article  PubMed  Google Scholar 

  128. Liu, J., Wang, L., Zhao, F., et al. (2015). Pre-clinical development of a humanized anti-CD47 antibody with anti-cancer therapeutic potential. PLoS ONE, 10, e0137345.

    Article  PubMed  PubMed Central  Google Scholar 

  129. Feng, M., Marjon, K. D., Zhu, F., et al. (2018). Programmed cell removal by calreticulin in tissue homeostasis and cancer. Nature Communications, 9, 3194.

    Article  PubMed  PubMed Central  Google Scholar 

  130. Bian, Z., Shi, L., Guo, Y. L., et al. (2016). Cd47-Sirpα interaction and IL-10 constrain inflammation-induced macrophage phagocytosis of healthy self-cells. Proc Natl Acad Sci U S A., 113, E5434-5443.

    Article  PubMed  PubMed Central  Google Scholar 

  131. Lehrman, E. K., Wilton, D. K., Litvina, E. Y., et al. (2018). CD47 Protects Synapses from Excess Microglia-Mediated Pruning during Development. Neuron, 100, 120-134.e126.

    Article  PubMed  PubMed Central  Google Scholar 

  132. Logtenberg, M. E. W., Scheeren, F. A., & Schumacher, T. N. (2020). The CD47-SIRPα Immune Checkpoint. Immunity, 52, 742–752.

    Article  PubMed  PubMed Central  Google Scholar 

  133. Maile, L. A., DeMambro, V. E., Wai, C., et al. (2011). An essential role for the association of CD47 to SHPS-1 in skeletal remodeling. Journal of Bone and Mineral Research, 26, 2068–2081.

    Article  PubMed  Google Scholar 

  134. Ding, X., Wang, J., Huang, M., et al. (2021). Loss of microglial SIRPα promotes synaptic pruning in preclinical models of neurodegeneration. Nature Communications, 12, 2030.

    Article  PubMed  PubMed Central  Google Scholar 

  135. Sato-Hashimoto, M., Saito, Y., Ohnishi, H., et al. (2011). Signal regulatory protein α regulates the homeostasis of T lymphocytes in the spleen. The Journal of Immunology, 187, 291–297.

    Article  PubMed  Google Scholar 

  136. Latour, S., Tanaka, H., Demeure, C., et al. (2001). Bidirectional negative regulation of human T and dendritic cells by CD47 and its cognate receptor signal-regulator protein-alpha: Down-regulation of IL-12 responsiveness and inhibition of dendritic cell activation. The Journal of Immunology, 167, 2547–2554.

    Article  PubMed  Google Scholar 

  137. Liu, Y., Merlin, D., Burst, S. L., Pochet, M., Madara, J. L., & Parkos, C. A. (2001). The role of CD47 in neutrophil transmigration. Increased rate of migration correlates with increased cell surface expression of CD47. J Biol Chem, 276, 40156–40166.

  138. Saito, Y., Iwamura, H., Kaneko, T., et al. (2010). Regulation by SIRPα of dendritic cell homeostasis in lymphoid tissues. Blood, 116, 3517–3525.

    Article  PubMed  Google Scholar 

  139. Meng, Z., Wang, Z., Guo, B., Cao, W., & Shen, H. (2019). TJC4, a differentiated anti-CD47 antibody with novel epitope and RBC sparing properties. Blood, 134, 4063.

    Article  Google Scholar 

  140. Mehta, A., Harb, W., Xu, C., et al. (2021). Lemzoparlimab, a differentiated anti-CD47 antibody in combination with rituximab in relapsed and refractory non-Hodgkin’s lymphoma: Initial clinical results. Blood, 138, 3542.

    Article  Google Scholar 

  141. Wilson, C., Bouchlaka, M., Puro, R., et al. (2019). Abstract B100: AO-176, a highly differentiated humanized anti-CD47 antibody, exhibits single-agent and combination antitumor efficacy with chemotherapy and targeted antibodies. Molecular Cancer Therapeutics, 18, B100–B100.

    Article  Google Scholar 

  142. Puro, R. J., Bouchlaka, M. N., Hiebsch, R. R., et al. (2020). Development of AO-176, a next-generation humanized anti-CD47 antibody with novel anticancer properties and negligible red blood cell binding. Molecular Cancer Therapeutics, 19, 835–846.

    Article  PubMed  Google Scholar 

  143. III HAB, Spira, A. I., Taylor, M. H., et al. (2021). A first-in-human study of AO-176, a highly differentiated anti-CD47 antibody, in patients with advanced solid tumors. Journal of Clinical Oncology, 39, 2516–2516.

  144. Osorio, J. C., Smith, P., Knorr, D. A., & Ravetch, J. V. (2023). The antitumor activities of anti-CD47 antibodies require Fc-FcγR interactions. Cancer Cell, 41, 2051-2065.e2056.

    Article  PubMed  PubMed Central  Google Scholar 

  145. Ma, L., Zhu, M., Gai, J., et al. (2020). Preclinical development of a novel CD47 nanobody with less toxicity and enhanced anti-cancer therapeutic potential. J Nanobiotechnology., 18, 12.

    Article  PubMed  PubMed Central  Google Scholar 

  146. Wang, Z., Cao, W., Guo, T., & Zang, J. (2018). Abstract 5622: A novel immunocytokine fusion protein combining tumor-targeting anti-CD47 antibody with GM-CSF cytokine for enhanced antitumor efficacy. Cancer Research., 78, 5622–5622.

    Article  Google Scholar 

  147. Guo, Y., Bao, Q., Hu, P., & Shi, J. (2023). Nanomedicine-based co-delivery of a calcium channel inhibitor and a small molecule targeting CD47 for lung cancer immunotherapy. Nature Communications, 14, 7306.

    Article  PubMed  PubMed Central  Google Scholar 

  148. Marks, J. D., Griffiths, A. D., Malmqvist, M., Clackson, T. P., Bye, J. M., & Winter, G. (1992). By-passing immunization: Building high affinity human antibodies by chain shuffling. Biotechnology (N. Y), 10, 779–783.

    PubMed  Google Scholar 

  149. Petrova, P. S., Viller, N. N., Wong, M., et al. (2017). TTI-621 (SIRPαFc): A CD47-blocking innate immune checkpoint inhibitor with broad antitumor activity and minimal erythrocyte binding. Clinical Cancer Research, 23, 1068–1079.

    Article  PubMed  Google Scholar 

  150. Lakhani, N. J., Chow, L. Q. M., Gainor, J. F., et al. (2021). Evorpacept alone and in combination with pembrolizumab or trastuzumab in patients with advanced solid tumours (ASPEN-01): A first-in-human, open-label, multicentre, phase 1 dose-escalation and dose-expansion study. The lancet Oncology, 22, 1740–1751.

    Article  PubMed  Google Scholar 

  151. Lin, G. H. Y., Chai, V., Lee, V., et al. (2017). TTI-621 (SIRPαFc), a CD47-blocking cancer immunotherapeutic, triggers phagocytosis of lymphoma cells by multiple polarized macrophage subsets. PLoS ONE, 12, e0187262.

    Article  PubMed  PubMed Central  Google Scholar 

  152. Ansell, S. M., Maris, M. B., Lesokhin, A. M., et al. (2021). Phase I study of the CD47 blocker TTI-621 in patients with relapsed or refractory hematologic malignancies. Clinical Cancer Research, 27, 2190–2199.

    Article  PubMed  Google Scholar 

  153. Horwitz, S. M., Foran, J. M., Maris, M., et al. (2021). Updates from ongoing, first-in-human phase 1 dose escalation and expansion study of TTI-621, a novel biologic targeting CD47, in patients with relapsed or refractory hematologic malignancies. Blood, 138, 2448.

    Article  Google Scholar 

  154. Sun, M., Qi, J., Zheng, W., et al. (2021). Preliminary results of a first-in-human phase I dtudy of IMM01, SIRPα Fc protein in patients with relapsed or refractory lymphoma. Journal of Clinical Oncology., 39, 2550–2550.

    Article  Google Scholar 

  155. Candas-Green, D., Xie, B., Huang, J., et al. (2020). Dual blockade of CD47 and HER2 eliminates radioresistant breast cancer cells. Nature Communications, 11, 4591.

    Article  PubMed  PubMed Central  Google Scholar 

  156. Koh, E., Lee, E. J., Nam, G. H., et al. (2017). Exosome-SIRPα, a CD47 blockade increases cancer cell phagocytosis. Biomaterials, 121, 121–129.

    Article  PubMed  Google Scholar 

  157. Liu, J., Meng, Z., Xu, T., et al. (2022). A SIRPαFc fusion protein conjugated with the collagen-binding domain for targeted immunotherapy of non-small cell lung cancer. Frontiers in Immunology, 13, 845217.

    Article  PubMed  PubMed Central  Google Scholar 

  158. Dheilly, E., Moine, V., Broyer, L., et al. (2017). Selective blockade of the ubiquitous checkpoint receptor CD47 is enabled by dual-targeting bispecific antibodies. Molecular Therapy, 25, 523–533.

    Article  PubMed  PubMed Central  Google Scholar 

  159. Piccione, E. C., Juarez, S., Liu, J., et al. (2015). A bispecific antibody targeting CD47 and CD20 selectively binds and eliminates dual antigen expressing lymphoma cells. MAbs, 7, 946–956.

    Article  PubMed  PubMed Central  Google Scholar 

  160. Bartley, A. N., Washington, M. K., Colasacco, C., et al. (2017). HER2 testing and clinical decision making in gastroesophageal adenocarcinoma: Guideline From the College of American Pathologists, American Society for Clinical Pathology, and the American Society of Clinical Oncology. Journal of Clinical Oncology, 35, 446–464.

    Article  PubMed  Google Scholar 

  161. Zhang, B., Li, S., Chen, D., et al. (2023). Abstract 2938: Preclinical development of a novel bispecific mAb-Trap fusion protein, IMM2902, targeting both HER2 and CD47 as cancer immunotherapy. Cancer Research., 83, 2938–2938.

    Article  Google Scholar 

  162. Zhang, B., Shi, J., Shi, X., et al. (2024). Development and evaluation of a human CD47/HER2 bispecific antibody for Trastuzumab-resistant breast cancer immunotherapy. Drug Resist Updat., 74, 101068.

    Article  PubMed  Google Scholar 

  163. Meng, Y., Zhang, J., Zhao, C., et al. (2023). Preliminary results of a phase I, first-in-human, dose escalation study of IMM2902 in patients with HER2-expressing advanced solid tumors. Journal of Clinical Oncology., 41, e15185–e15185.

    Article  Google Scholar 

  164. Overman, M. J., Melhem, R., Blum-Murphy, M. A., et al. (2023). A phase I, first-in-human, open-label, dose escalation and expansion study of PT886 in adult patients with advanced gastric, gastroesophageal junction, and pancreatic adenocarcinomas. Journal of Clinical Oncology, 41, TPS765-TPS765.

  165. Overman, M. J., Laeufle, R., Singh, H., et al. (2024). 1531TiP TWINPEAK phase I/II study, PT886 a bispecific antibody targeting claudin 18.2 and CD47 in combination with chemotherapy and/or pembrolizumab in gastric/GEJ-carcinomas or PDAC. Annals of Oncology, 35, S933-S934.

  166. Weidemann, S., Gagelmann, P., Gorbokon, N., et al. (2021). Mesothelin expression in human tumors: A tissue microarray study on 12,679 tumors. Biomedicines, 9.

  167. Romano, E., Medioni, J., Rouge, T. D. L. M., et al. (2022). 707 A phase 1, open-label, dose finding study of NI-1801, a bispecific mesothelin x CD47 engaging antibody, in patients with mesothelin expressing solid cancers. Journal for Immunotherapy of Cancer, 10, A740–A740.

    Google Scholar 

  168. Houvast, R. D., van Duijvenvoorde, M., Thijse, K., et al. (2024). Selecting targets for molecular imaging of gastric cancer: An immunohistochemical evaluation. Mol Diagn Ther.

  169. Seckinger, A., Buatois, V., Moine, V., et al. (2024). Targeting CEACAM5-positive solid tumors using NILK-2401, a novel CEACAM5xCD47 κλ bispecific antibody. Frontiers in Immunology, 15, 1378813.

    Article  PubMed  PubMed Central  Google Scholar 

  170. Du, K., Li, Y., Liu, J., et al. (2021). A bispecific antibody targeting GPC3 and CD47 induced enhanced antitumor efficacy against dual antigen-expressing HCC. Molecular Therapy, 29, 1572–1584.

    Article  PubMed  PubMed Central  Google Scholar 

  171. Yi, N., Yin, X., Feng, X., Ren, M., & Ma, C. (2024). Identification of gastric cancer subtypes based on disulfidptosis-related genes: GPC3 as a novel biomarker for prognosis prediction. Discov Oncol., 15, 810.

    Article  PubMed  PubMed Central  Google Scholar 

  172. Weiskopf, K. (2017). Cancer immunotherapy targeting the CD47/SIRPα axis. European Journal of Cancer, 76, 100–109.

    Article  PubMed  Google Scholar 

  173. Liu, J., Xavy, S., Mihardja, S., et al. (2020). Targeting macrophage checkpoint inhibitor SIRPα for anticancer therapy. JCI Insight, 5.

  174. Brown, E. J., & Frazier, W. A. (2001). Integrin-associated protein (CD47) and its ligands. Trends in Cell Biology, 11, 130–135.

    Article  PubMed  Google Scholar 

  175. Bian, Z., Shi, L., Kidder, K., Zen, K., Garnett-Benson, C., & Liu, Y. (2021). Intratumoral SIRPα-deficient macrophages activate tumor antigen-specific cytotoxic T cells under radiotherapy. Nature Communications, 12, 3229.

    Article  PubMed  PubMed Central  Google Scholar 

  176. Gauttier, V., Pengam, S., Durand, J., et al. (2020). Selective SIRPα blockade reverses tumor T cell exclusion and overcomes cancer immunotherapy resistance. The Journal of Clinical Investigation, 130, 6109–6123.

    Article  PubMed  PubMed Central  Google Scholar 

  177. Ring, N. G., Herndler-Brandstetter, D., Weiskopf, K., et al. (2017). Anti-SIRPα antibody immunotherapy enhances neutrophil and macrophage antitumor activity. Proc Natl Acad Sci U S A., 114, E10578-e10585.

    Article  PubMed  PubMed Central  Google Scholar 

  178. Chan, H., Trout, C., Mikolon, D., et al. (2021). Discovery and preclinical characterization of CC-95251, an Anti-SIRPα antibody that enhances macrophage-mediated phagocytosis of non-Hodgkin lymphoma (NHL) cells when combined with rituximab. Blood, 138, 2271–2271.

    Article  Google Scholar 

  179. Sue, M., Tsubaki, T., Ishimoto, Y., et al. (2024). Blockade of SIRPα-CD47 axis by anti-SIRPα antibody enhances anti-tumor activity of DXd antibody-drug conjugates. PLoS ONE, 19, e0304985.

    Article  PubMed  PubMed Central  Google Scholar 

  180. Logtenberg, M. E. W., Jansen, J. H. M., Raaben, M., et al. (2019). Glutaminyl cyclase is an enzymatic modifier of the CD47- SIRPα axis and a target for cancer immunotherapy. Nature Medicine, 25, 612–619.

    Article  PubMed  PubMed Central  Google Scholar 

  181. Wu, Z., Weng, L., Zhang, T., et al. (2019). Identification of glutaminyl cyclase isoenzyme isoQC as a regulator of SIRPα-CD47 axis. Cell Research, 29, 502–505.

    Article  PubMed  PubMed Central  Google Scholar 

  182. Cynis, H., Rahfeld, J. U., Stephan, A., et al. (2008). Isolation of an isoenzyme of human glutaminyl cyclase: Retention in the Golgi complex suggests involvement in the protein maturation machinery. Journal of Molecular Biology, 379, 966–980.

    Article  PubMed  Google Scholar 

  183. Lues, I., Weber, F., Meyer, A., et al. (2015). A phase 1 study to evaluate the safety and pharmacokinetics of PQ912, a glutaminyl cyclase inhibitor, in healthy subjects. Alzheimers Dement (N Y)., 1, 182–195.

    Article  PubMed  Google Scholar 

  184. Scheltens, P., Hallikainen, M., Grimmer, T., et al. (2018). Safety, tolerability and efficacy of the glutaminyl cyclase inhibitor PQ912 in Alzheimer’s disease: Results of a randomized, double-blind, placebo-controlled phase 2a study. Alzheimers Res Ther., 10, 107.

    Article  PubMed  PubMed Central  Google Scholar 

  185. Song, Z., Tong, X., Zhang, Y., et al. (2023). IMM01 plus tislelizumab in patients with advanced solid tumors and lymphoma: An open-label, multicenter, phase 1b/2 dose escalation and expansion study (IMM01-04). Journal of Clinical Oncology., 41, 2600–2600.

    Article  Google Scholar 

  186. Zhao, X. W., van Beek, E. M., Schornagel, K., et al. (2011). CD47-signal regulatory protein-α (SIRPα) interactions form a barrier for antibody-mediated tumor cell destruction. Proc Natl Acad Sci U S A., 108, 18342–18347.

    Article  PubMed  PubMed Central  Google Scholar 

  187. Treffers, L. W., Zhao, X. W., van der Heijden, J., et al. (2018). Genetic variation of human neutrophil Fcγ receptors and SIRPα in antibody-dependent cellular cytotoxicity towards cancer cells. European Journal of Immunology, 48, 344–354.

    Article  PubMed  Google Scholar 

  188. Bang, Y. J., Van Cutsem, E., Feyereislova, A., et al. (2010). Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial. Lancet, 376, 687–697.

    Article  PubMed  Google Scholar 

  189. Lordick, F., Carneiro, F., Cascinu, S., et al. (2022). Gastric cancer: ESMO clinical practice guideline for diagnosis, treatment and follow-up. Annals of Oncology, 33, 1005–1020.

    Article  PubMed  Google Scholar 

  190. Janjigian, Y. Y., Kawazoe, A., Bai, Y., et al. (2024). Pembrolizumab in HER2-positive gastric cancer. New England Journal of Medicine, 391, 1360–1362.

    Article  PubMed  Google Scholar 

  191. Matlung, H. L., Babes, L., Zhao, X. W., et al. (2018). Neutrophils kill antibody-opsonized cancer cells by trogoptosis. Cell Reports, 23, 3946-3959.e3946.

    Article  PubMed  Google Scholar 

  192. Kauder, S. E., Kuo, T. C., Harrabi, O., et al. (2018). ALX148 blocks CD47 and enhances innate and adaptive antitumor immunity with a favorable safety profile. PLoS ONE, 13, e0201832.

    Article  PubMed  PubMed Central  Google Scholar 

  193. Upton, R., Banuelos, A., Feng, D., et al. (2021). Combining CD47 blockade with trastuzumab eliminates HER2-positive breast cancer cells and overcomes trastuzumab tolerance. Proc Natl Acad Sci U S A, 118.

  194. Tsao, L. C., Crosby, E. J., Trotter, T. N., et al. (2019). CD47 blockade augmentation of trastuzumab antitumor efficacy dependent on antibody-dependent cellular phagocytosis. JCI Insight, 4.

  195. Chow, L. Q. M., Gainor, J. F., Lakhani, N. J., et al. (2020). A phase I study of ALX148, a CD47 blocker, in combination with standard anticancer antibodies and chemotherapy regimens in patients with advanced malignancy. Journal of Clinical Oncology., 38, 3056–3056.

    Article  Google Scholar 

  196. Makiyama, A., Sukawa, Y., Kashiwada, T., et al. (2020). Randomized, phase II study of trastuzumab beyond progression in patients with HER2-positive advanced gastric or gastroesophageal junction cancer: WJOG7112G (T-ACT Study). Journal of Clinical Oncology, 38, 1919–1927.

    Article  PubMed  Google Scholar 

  197. Chung, H., Lee, K., Kim, W., et al. (2021). SO-31 ASPEN-01: A phase 1 study of ALX148, a CD47 blocker, in combination with trastuzumab, ramucirumab and paclitaxel in patients with second-line HER2-positive advanced gastric or gastroesophageal junction cancer. Annals of Oncology., 32, S215–S216.

    Article  Google Scholar 

  198. Seo, S., Ryu, M. H., Park, Y. S., et al. (2019). Loss of HER2 positivity after anti-HER2 chemotherapy in HER2-positive gastric cancer patients: Results of the GASTric cancer HER2 reassessment study 3 (GASTHER3). Gastric Cancer, 22, 527–535.

    Article  PubMed  Google Scholar 

  199. Saeki, H., Oki, E., Kashiwada, T., et al. (2018). Re-evaluation of HER2 status in patients with HER2-positive advanced or recurrent gastric cancer refractory to trastuzumab (KSCC1604). European Journal of Cancer, 105, 41–49.

    Article  PubMed  Google Scholar 

  200. Wilke, H., Muro, K., Van Cutsem, E., et al. (2014). Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): A double-blind, randomised phase 3 trial. The lancet Oncology, 15, 1224–1235.

    Article  PubMed  Google Scholar 

  201. Lordick, F., Kang, Y. K., Chung, H. C., et al. (2013). Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): A randomised, open-label phase 3 trial. The lancet Oncology, 14, 490–499.

    Article  PubMed  Google Scholar 

  202. Dutton, S. J., Ferry, D. R., Blazeby, J. M., et al. (2014). Gefitinib for oesophageal cancer progressing after chemotherapy (COG): A phase 3, multicentre, double-blind, placebo-controlled randomised trial. The lancet Oncology, 15, 894–904.

    Article  PubMed  Google Scholar 

  203. Waddell, T., Chau, I., Cunningham, D., et al. (2013). Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): A randomised, open-label phase 3 trial. The lancet Oncology, 14, 481–489.

    Article  PubMed  PubMed Central  Google Scholar 

  204. Lordick, F., Kang, Y.-K., Salman, P., et al. Clinical outcome according to tumor HER2 status and EGFR expression in advanced gastric cancer patients from the EXPAND study. Journal of Clinical Oncology 31, 4021–4021.

  205. Petty, R. D., Dahle-Smith, A., Stevenson, D. A. J., et al. (2017). Gefitinib and EGFR gene copy number aberrations in esophageal cancer. Journal of Clinical Oncology, 35, 2279–2287.

    Article  PubMed  Google Scholar 

  206. Maron, S. B., Moya, S., Morano, F., et al. (2022). Epidermal growth factor receptor inhibition in epidermal growth factor receptor-amplified gastroesophageal cancer: Retrospective global experience. Journal of Clinical Oncology, 40, 2458–2467.

    Article  PubMed  PubMed Central  Google Scholar 

  207. Corso, S., Pietrantonio, F., Apicella, M., et al. (2021). Optimized EGFR blockade strategies in EGFR addicted gastroesophageal adenocarcinomas. Clinical Cancer Research, 27, 3126–3140.

    Article  PubMed  Google Scholar 

  208. Li, B., Hao, Y., He, H., et al. (2024). CD47-SIRPα blockade sensitizes head and neck squamous cell carcinoma to cetuximab by enhancing macrophage adhesion to cancer cells. Cancer Res.

  209. Fisher, G. A., Lakhani, N. J., Eng, C., et al. (2020). A phase Ib/II study of the anti-CD47 antibody magrolimab with cetuximab in solid tumor and colorectal cancer patients. Journal of Clinical Oncology., 38, 114–114.

    Article  Google Scholar 

  210. Wainberg, Z. A., Enzinger, P. C., Kang, Y. K., et al. (2022). Bemarituzumab in patients with FGFR2b-selected gastric or gastro-oesophageal junction adenocarcinoma (FIGHT): A randomised, double-blind, placebo-controlled, phase 2 study. The lancet Oncology, 23, 1430–1440.

    Article  PubMed  Google Scholar 

  211. Rha, S. Y., Zhang, Y., Elme, A., et al. (2025). Prevalence of FGFR2b protein overexpression in advanced gastric cancers during prescreening for the phase III FORTITUDE-101 Trial. JCO Precision Oncology, 9, e2400710.

    Article  PubMed  Google Scholar 

  212. Pierce, K. L., Deshpande, A. M., Stohr, B. A., et al. (2014). FPA144, a humanized monoclonal antibody for both <i>FGFR2</i>-amplified and nonamplified, <i>FGFR2b</i>-overexpressing gastric cancer patients. Journal of Clinical Oncology., 32, e15074–e15074.

    Article  Google Scholar 

  213. Powers, J., Palencia, S., Foy, S., et al. (2016). Abstract 1407: FPA144, a therapeutic monoclonal antibody targeting the FGFR2b receptor, promotes antibody dependent cell-mediated cytotoxicity and stimulates sensitivity to PD-1 in the 4T1 syngeneic tumor model. Cancer Research., 76, 1407–1407.

    Article  Google Scholar 

  214. Sahin, U., Schuler, M., Richly, H., et al. (2018). A phase I dose-escalation study of IMAB362 (Zolbetuximab) in patients with advanced gastric and gastro-oesophageal junction cancer. European Journal of Cancer, 100, 17–26.

    Article  PubMed  Google Scholar 

  215. Shitara, K., Lordick, F., Bang, Y. J., et al. (2023). Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): A multicentre, randomised, double-blind, phase 3 trial. Lancet, 401, 1655–1668.

  216. Shah, M. A., Shitara, K., Ajani, J. A., et al. (2023). Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: The randomized, phase 3 GLOW trial. Nat Med 29, 2133–2141.

  217. Shitara, K., Shah, M. A., Lordick, F., et al. (2024). Zolbetuximab in gastric or gastroesophageal junction adenocarcinoma. New England Journal of Medicine, 391, 1159–1162.

    Article  PubMed  Google Scholar 

  218. Getu, A. A., Tigabu, A., Zhou, M., Lu, J., Fodstad, Ø., & Tan, M. (2023). New frontiers in immune checkpoint B7–H3 (CD276) research and drug development. Molecular Cancer, 22, 43.

    Article  PubMed  PubMed Central  Google Scholar 

  219. Singh, R., Kim, Y. H., Lee, S. J., Eom, H. S., & Choi, B. K. (2024). 4–1BB immunotherapy: Advances and hurdles. Experimental & Molecular Medicine, 56, 32–39.

    Article  Google Scholar 

  220. Tao, H., Qian, P., Wang, F., Yu, H., & Guo, Y. (2017). Targeting CD47 enhances the efficacy of anti-PD-1 and CTLA-4 in an esophageal squamous cell cancer preclinical model. Oncology Research, 25, 1579–1587.

    Article  PubMed  PubMed Central  Google Scholar 

  221. Pardoll, D. M. (2012). The blockade of immune checkpoints in cancer immunotherapy. Nature Reviews Cancer, 12, 252–264.

    Article  PubMed  PubMed Central  Google Scholar 

  222. Hendriks, M., Britsch, I., Ke, X., et al. (2021). Cancer cells under immune attack acquire CD47-mediated adaptive immune resistance independent of the myeloid CD47-SIRPα axis. Oncoimmunology., 10, 2005344.

    Article  PubMed  PubMed Central  Google Scholar 

  223. Manguso, R. T., Pope, H. W., Zimmer, M. D., et al. (2017). In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target. Nature, 547, 413–418.

    Article  PubMed  PubMed Central  Google Scholar 

  224. Liu, X., Liu, L., Ren, Z., et al. (2018). Dual targeting of innate and adaptive checkpoints on tumor cells limits immune evasion. Cell Reports, 24, 2101–2111.

    Article  PubMed  Google Scholar 

  225. Lian, S., Xie, R., Ye, Y., et al. (2019). Simultaneous blocking of CD47 and PD-L1 increases innate and adaptive cancer immune responses and cytokine release. eBioMedicine, 42, 281–295.

    Article  PubMed  PubMed Central  Google Scholar 

  226. Daginakatte, G., Pottayil, S., Chennakrishna, G., et al. (2018). Abstract 3852: Combination efficacy and safety profile of an orally bioavailable small molecule agent targeting CD47/SIRPα axis. Cancer Research., 78, 3852–3852.

    Article  Google Scholar 

  227. Yanagita, T., Murata, Y., Tanaka, D., et al. (2017). Anti-SIRPα antibodies as a potential new tool for cancer immunotherapy. JCI Insight., 2, e89140.

    Article  PubMed  PubMed Central  Google Scholar 

  228. Chen, S. H., Dominik, P. K., Stanfield, J., et al. (2021). Dual checkpoint blockade of CD47 and PD-L1 using an affinity-tuned bispecific antibody maximizes antitumor immunity. J Immunother Cancer, 9.

  229. Deng, L., Liang, H., Xu, M., et al. (2014). STING-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors. Immunity, 41, 843–852.

    Article  PubMed  PubMed Central  Google Scholar 

  230. Wang, R., Zhang, C., Cao, Y., et al. (2023). Blockade of dual immune checkpoint inhibitory signals with a CD47/PD-L1 bispecific antibody for cancer treatment. Theranostics., 13, 148–160.

    Article  PubMed  PubMed Central  Google Scholar 

  231. Wang, Y., Ni, H., Zhou, S., et al. (2021). Tumor-selective blockade of CD47 signaling with a CD47/PD-L1 bispecific antibody for enhanced anti-tumor activity and limited toxicity. Cancer Immunology, Immunotherapy, 70, 365–376.

    Article  PubMed  Google Scholar 

  232. Roohullah, A., Ganju, V., Zhang, F., et al. (2021). First-in-human phase 1 dose escalation study of HX009, a novel recombinant humanized anti-PD-1 and CD47 bispecific antibody, in patients with advanced malignancies. Journal of Clinical Oncology., 39, 2517–2517.

    Article  Google Scholar 

  233. Carneiro, B. A., Safran, H., Beck, J. T. T., et al. (2023). Phase 1 first-in-human study of PF-07257876, a novel CD47/PD-L1 bispecific checkpoint inhibitor, in patients with PD-1/PD-L1-refractory and -naïve advanced solid tumors. Journal of Clinical Oncology., 41, 2529–2529.

    Article  Google Scholar 

  234. Ribas, A., & Wolchok, J. D. (2018). Cancer immunotherapy using checkpoint blockade. Science, 359, 1350–1355.

    Article  PubMed  PubMed Central  Google Scholar 

  235. Song, X., Lu, Z., & Xu, J. (2020). Targeting cluster of differentiation 47 improves the efficacy of anti-cytotoxic T-lymphocyte associated protein 4 treatment via antigen presentation enhancement in pancreatic ductal adenocarcinoma. Experimental and Therapeutic Medicine, 20, 3301–3309.

    PubMed  PubMed Central  Google Scholar 

  236. Xia, Q., Wu, T., Wang, F., et al. (2023). The safety and efficacy of cadonilimab in combination with AK117 (anti-CD47 antibody) plus chemotherapy as first-line treatment for advanced gastric (G) or gastroesophageal junction (GEJ) cancer. Journal of Clinical Oncology., 41, e16050–e16050.

    Article  Google Scholar 

  237. Zhang, A., Ren, Z., Tseng, K. F., et al. (2021). Dual targeting of CTLA-4 and CD47 on T(reg) cells promotes immunity against solid tumors. Sci Transl Med, 13.

  238. Barkal, A. A., Weiskopf, K., Kao, K. S., et al. (2018). Engagement of MHC class I by the inhibitory receptor LILRB1 suppresses macrophages and is a target of cancer immunotherapy. Nature Immunology, 19, 76–84.

    Article  PubMed  Google Scholar 

  239. Barkal, A. A., Brewer, R. E., Markovic, M., et al. (2019). CD24 signalling through macrophage Siglec-10 is a target for cancer immunotherapy. Nature, 572, 392–396.

    Article  PubMed  PubMed Central  Google Scholar 

  240. Zhang, W., Zeng, Y., Xiao, Q., et al. (2024). An in-situ peptide-antibody self-assembly to block CD47 and CD24 signaling enhances macrophage-mediated phagocytosis and anti-tumor immune responses. Nature Communications, 15, 5670.

    Article  PubMed  PubMed Central  Google Scholar 

  241. Gozlan, Y. M., Hilgendorf, S., Aronin, A., et al. (2019). Abstract A076: DSP107—a novel SIRPα-4-1BBL dual signaling protein (DSP) for cancer immunotherapy. Cancer Immunology Research, 7, A076–A076.

    Article  Google Scholar 

  242. Saeed, A., Zhang, J., Bashir, B., et al. (2024). 51P Phase II dose expansion study of DSP107, a first-in-class fusion protein targeting CD47 and 4–1BB, in combination with atezolizumab in patients with advanced MSS colorectal cancer. Annals of Oncology., 35, S25.

    Article  Google Scholar 

  243. Gao, J., Wang, Z., Jiang, W., et al. (2023). CLDN18.2 and 4–1BB bispecific antibody givastomig exerts antitumor activity through CLDN18.2-expressing tumor-directed T-cell activation. J Immunother Cancer, 11.

  244. Chen, Y., Yu, Z., Tan, X., et al. (2021). CAR-macrophage: A new immunotherapy candidate against solid tumors. Biomedicine & Pharmacotherapy, 139, 111605.

    Article  Google Scholar 

  245. Chen, Y., Zhu, X., Liu, H., et al. (2023). The application of HER2 and CD47 CAR-macrophage in ovarian cancer. Journal of Translational Medicine, 21, 654.

    Article  PubMed  PubMed Central  Google Scholar 

  246. Zhang, W., Huang, Q., Xiao, W., et al. (2020). Advances in anti-tumor treatments targeting the CD47/SIRPα axis. Frontiers in Immunology, 11, 18.

    Article  PubMed  PubMed Central  Google Scholar 

  247. Chou, C. W., Hung, C. N., Chiu, C. H., et al. (2023). Phagocytosis-initiated tumor hybrid cells acquire a c-Myc-mediated quasi-polarization state for immunoevasion and distant dissemination. Nature Communications, 14, 6569.

    Article  PubMed  PubMed Central  Google Scholar 

  248. Aguirre, L. A., Montalbán-Hernández, K., Avendaño-Ortiz, J., et al. (2020). Tumor stem cells fuse with monocytes to form highly invasive tumor-hybrid cells. Oncoimmunology., 9, 1773204.

    Article  PubMed  PubMed Central  Google Scholar 

  249. Sutton, T. L., Patel, R. K., Anderson, A. N., et al. (2022). Circulating cells with macrophage-like characteristics in cancer: The importance of circulating neoplastic-immune hybrid cells in cancer. Cancers (Basel), 14.

  250. Yu, J., Song, Y., & Tian, W. (2020). How to select IgG subclasses in developing anti-tumor therapeutic antibodies. Journal of Hematology & Oncology, 13, 45.

    Article  Google Scholar 

  251. Zheng, F., Zhang, W., Yang, B., & Chen, M. (2022). Multi-omics profiling identifies C1QA/B(+) macrophages with multiple immune checkpoints associated with esophageal squamous cell carcinoma (ESCC) liver metastasis. Ann Transl Med., 10, 1249.

    Article  PubMed  PubMed Central  Google Scholar 

  252. Huang, C., Wang, X., Wang, Y., et al. (2024). Sirpα on tumor-associated myeloid cells restrains antitumor immunity in colorectal cancer independent of its interaction with CD47. Nat Cancer., 5, 500–516.

    Article  PubMed  Google Scholar 

  253. Shalem, O., Sanjana, N. E., & Zhang, F. (2015). High-throughput functional genomics using CRISPR-Cas9. Nature Reviews Genetics, 16, 299–311.

    Article  PubMed  PubMed Central  Google Scholar 

  254. Mair, B., Aldridge, P. M., Atwal, R. S., et al. (2019). High-throughput genome-wide phenotypic screening via immunomagnetic cell sorting. Nat Biomed Eng., 3, 796–805.

    Article  PubMed  Google Scholar 

  255. Zhou, H., Wang, W., Xu, H., et al. (2024). Metabolic reprograming mediated by tumor cell-intrinsic type I IFN signaling is required for CD47-SIRPα blockade efficacy. Nature Communications, 15, 5759.

    Article  PubMed  PubMed Central  Google Scholar 

  256. Jiang, P., Lagenaur, C. F., & Narayanan, V. (1999). Integrin-associated protein is a ligand for the P84 neural adhesion molecule. Journal of Biological Chemistry, 274, 559–562.

    Article  PubMed  Google Scholar 

  257. Bournazos, S. (2019). IgG Fc receptors: Evolutionary considerations. Current Topics in Microbiology and Immunology, 423, 1–11.

    PubMed  Google Scholar 

  258. Subramanian, S., Parthasarathy, R., Sen, S., Boder, E. T., & Discher, D. E. (2006). Species- and cell type-specific interactions between CD47 and human SIRPalpha. Blood, 107, 2548–2556.

    Article  PubMed  PubMed Central  Google Scholar 

  259. Iwamoto, C., Takenaka, K., Urata, S., et al. (2014). The BALB/c-specific polymorphic SIRPA enhances its affinity for human CD47, inhibiting phagocytosis against human cells to promote xenogeneic engraftment. Experimental Hematology, 42, 163-171.e161.

    Article  PubMed  Google Scholar 

  260. Edris, B., Weiskopf, K., Volkmer, A. K., et al. (2012). Antibody therapy targeting the CD47 protein is effective in a model of aggressive metastatic leiomyosarcoma. Proc Natl Acad Sci U S A., 109, 6656–6661.

    Article  PubMed  PubMed Central  Google Scholar 

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  1. Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan

    Akira Ooki, Hiroki Osumi, Keitaro Shimozaki & Kensei Yamaguchi

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  1. Akira Ooki
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  2. Hiroki Osumi
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A.O. developed the conceptual frameworks, searched the literature, and wrote the manuscript. H.O., K.S., and K. Y. revised the manuscript.

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Ooki, A., Osumi, H., Shimozaki, K. et al. Novel immunotherapy for gastric cancer: targeting the CD47–SIRPα axis. Cancer Metastasis Rev 44, 52 (2025). https://doi.org/10.1007/s10555-025-10269-z

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