Open Access

COMMENTARY

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

Xuejun Guo^1,2, Yilin Fu³, Natalia Baran^4,5, Wenxue Ma^6,*

1 Department of Hematology, Puyang Oilfield General Hospital Affiliated to Henan Medical University, Puyang, 457001, China
2 Puyang Cell Therapy Engineering Technology Research Center, Puyang, 457001, China
3 China Medical University-the Queen’s University of Belfast Joint College, Shenyang, 110112, China
4 Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, Bern, 3012, Switzerland
5 Department of Internal Medicine, Sanford School of Medicine, University of South Dakota, Sioux Falls, South Dakota, Sioux Falls, SD 57104, USA
6 Department of Medicine, Sanford Stem Cell Institute, Moores Cancer Center, University of California San Diego, La Jolla, San Diego, CA 92093, USA

* Corresponding Author: Wenxue Ma. Email:

Oncology Research 2025, 33(11), 3375-3385. https://doi.org/10.32604/or.2025.071708

Received 11 August 2025; Accepted 22 September 2025; Issue published 22 October 2025

Abstract

Cluster of differentiation 47 (CD47), an immune checkpoint commonly referred to as the “don’t eat me” signal, plays a pivotal role in tumor immune evasion by inhibiting phagocytosis through interaction with signal regulatory protein alpha (SIRPα) on macrophages and dendritic cells (DCs). Although early enthusiasm drove broad clinical development, recent discontinuations of major CD47-targeted programs have prompted re-evaluation of its therapeutic potential. The purpose of this commentary is to contextualize the setbacks observed with first-generation CD47 inhibitors and to highlight strategies aimed at overcoming their limitations. Clinical challenges, including anemia, thrombocytopenia, suboptimal pharmacokinetics, and limited single-agent efficacy, underscore the need to develop safer, more selective approaches. Emerging next-generation strategies, such as SIRPα-directed agents, bispecific antibodies, and conditionally active therapeutics, are designed to enhance safety and tumor selectivity and reduce systemic toxicity. In addition, spatial profiling and biomarker-driven patient selection are advancing toward guiding rational therapeutic combinations, including with “eat-me” signals (e.g., calreticulin [CALR]) or DNA damage response therapies (e.g., poly(ADP-ribose) polymerase [PARP] inhibitors). Rather than signaling failure, these developments underscore the need for precision, context-specific applications, and adaptive trial designs to realize the durable therapeutic promise of CD47 blockade in cancer immunotherapy.

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Keywords

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