2. Academic Validation
  3. Targeting CD37 promotes macrophage-dependent phagocytosis of multiple cancer cell types and facilitates tumor clearance in mice

Targeting CD37 promotes macrophage-dependent phagocytosis of multiple cancer cell types and facilitates tumor clearance in mice

  • Nat Commun. 2025 Jul 18;16(1):6610. doi: 10.1038/s41467-025-61348-2.
Xinya Gao # 1 2 3 4,  Jing Zhang # 5 6,  Hui Zhang # 7,  Xin Liu # 6 8,  Bo Zeng 9,  Huijin Wang 6 8,  Hanbing Zhang 10,  Weng-Onn Lui 11,  Xiaoyan Hui 12,  Hongming Miao 13 14,  Jie Li 15 16 17
Affiliations

Affiliations

  • 1 Department of Breast Surgery, Cancer Hospital of Shantou University Medical College, Shantou, China. surgeong@163.com.
  • 2 Institute of Reproductive Health and Perinatology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China. surgeong@163.com.
  • 3 Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China. surgeong@163.com.
  • 4 Department of Thyroid and Breast Surgery, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China. surgeong@163.com.
  • 5 Department of Breast Surgery, Cancer Hospital of Shantou University Medical College, Shantou, China.
  • 6 Institute of Reproductive Health and Perinatology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
  • 7 Department of Breast Surgery, Fujian Provincial Hospital, Fuzhou, China.
  • 8 Department of Thyroid and Breast Surgery, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
  • 9 Department of Thoracic Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 10 Department of Neurosurgery, Shanghai Deji Hospital, Qingdao University, Shanghai, China.
  • 11 Department of Oncology-Pathology, Karolinska Institutet, BioClinicum, Karolinska University Hospital, Solna, Sweden.
  • 12 School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China.
  • 13 Department of Pathophysiology, College of High Altitude Military Medicine, Army Medical University, Chongqing, China. hongmingmiao@sina.com.
  • 14 Key Laboratory of Extreme Environmental Medicine, Ministry of Education of China, Chongqing, China. hongmingmiao@sina.com.
  • 15 Department of Breast Surgery, Cancer Hospital of Shantou University Medical College, Shantou, China. lijie2958@gwcmc.org.
  • 16 Institute of Reproductive Health and Perinatology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China. lijie2958@gwcmc.org.
  • 17 Department of Thyroid and Breast Surgery, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China. lijie2958@gwcmc.org.
  • # Contributed equally.
PMID: 40675974 DOI: 10.1038/s41467-025-61348-2
Abstract

Macrophages play vital roles in innate and adaptive immunity, and their functions are mediated via phagocytosis and antigen presentation. Despite the effort to identify phagocytic checkpoints and explore their mechanism of action, current checkpoint-scanning strategies cannot provide a complete and systematic list of such immune checkpoints. Here, we perform in vitro phagocytosis assays using primary healthy donor macrophages co-cultured with breast Cancer cells followed by ribosome profiling of sorted macrophages, to identify immune system-specific checkpoints. We observe a downregulation of CD37 in phagocytic macrophages and demonstrate that targeting CD37 with a specific antibody promotes the phagocytosis of multiple Cancer cells in vitro. Mechanistically, tumorous macrophage migration inhibitory factor (MIF) directly binds to CD37, promoting the phosphorylation of CD37Y13 and activating a transduction cascade that involves the recruitment of SHP1 and inhibition of Akt signaling, ultimately impairing phagocytosis. In vivo, targeting CD37 promotes tumor clearance in multiple preclinical mouse models and synergizes with anti-CD47 therapy. Thus, our study identifies a previously unidentified phagocytic checkpoint and provides new potential for precise therapy.

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