USP2 inhibition unleashes CD47-restrained phagocytosis and enhances anti-tumor immunity

  • Nat Commun. 2025 May 16;16(1):4564. doi: 10.1038/s41467-025-59621-5.
Panpan Dai  #  1 ,  Yishuang Sun  #  1  2 ,  Zhengrong Huang  #  3 ,  Yu-Tong Liu  #  4 ,  Minling Gao  1  2 ,  Hai-Ming Liu  4 ,  Jie Shi  1  2 ,  Chuan He  1  2 ,  Bolin Xiang  1  2 ,  Yingmeng Yao  1  2 ,  Haisheng Yu  1  2 ,  Gaoshan Xu  1  2 ,  Lijun Kong  1  2 ,  Xiangling Xiao  1  2 ,  Xiyong Wang  1  2 ,  Xue Zhang  1  2 ,  Wenjun Xiong  1  2 ,  Jing Hu  1 ,  Dandan Lin  5 ,  Bo Zhong  2  6 ,  Gang Chen  7  8  9 ,  Yan Gong  10 ,  Conghua Xie  11  12 ,  Jinfang Zhang  13  14
Affiliations
  • 1. Department of Radiation and Medical Oncology, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Hubei Key Laboratory of Tumor Biological Behavior, Hubei Provincial Clinical Research Center for Cancer, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.
  • 2. State Key Laboratory of Metabolism and Regulation in Complex Organisms, College of Life Sciences, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China.
  • 3. Tumor Precision Diagnosis and Treatment Technology and Translational Medicine, Hubei Engineering Research Center, Zhongnan Hospital of Wuhan University, Wuhan, China.
  • 4. State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China.
  • 5. Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China.
  • 6. Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, China.
  • 7. State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China. [email protected].
  • 8. Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, China. [email protected].
  • 9. Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, Wuhan, China. [email protected].
  • 10. Tumor Precision Diagnosis and Treatment Technology and Translational Medicine, Hubei Engineering Research Center, Zhongnan Hospital of Wuhan University, Wuhan, China. [email protected].
  • 11. Department of Radiation and Medical Oncology, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Hubei Key Laboratory of Tumor Biological Behavior, Hubei Provincial Clinical Research Center for Cancer, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China. [email protected].
  • 12. Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan, China. [email protected].
  • 13. Department of Radiation and Medical Oncology, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Hubei Key Laboratory of Tumor Biological Behavior, Hubei Provincial Clinical Research Center for Cancer, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China. [email protected].
  • 14. State Key Laboratory of Metabolism and Regulation in Complex Organisms, College of Life Sciences, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China. [email protected].
  • # Contributed equally.
PMID: 40379682 DOI: 10.1038/s41467-025-59621-5
Abstract

The CD47/SIRPα axis conveys a 'don't eat me' signal, thereby thwarting the phagocytic clearance of tumor cells. Although blocking antibodies targeting CD47 have demonstrated promising anti-tumor effects in preclinical models, clinical trials involving human Cancer patients have not yielded ideal results. Exploring the regulatory mechanisms of CD47 is imperative for devising more efficacious combinational therapies. Here, we report that inhibiting USP2 prompts CD47 degradation and reshapes the tumor microenvironment (TME), thereby enhancing anti-PD-1 immunotherapy. Mechanistically, USP2 interacts with CD47, stabilizing it through deubiquitination. USP2 inhibition destabilizes CD47, thereby boosting macrophage phagocytosis. Single-cell RNA Sequencing shows USP2 inhibition reprograms TME, evidenced by increasing M1 macrophages and CD8+ T cells while reducing M2 macrophages. Combining ML364 with anti-PD-1 reduces tumor burden in mouse models. Clinically, low USP2 expression predicts a better response to anti-PD-1 treatment. Our findings uncover the regulatory mechanism of CD47 by USP2 and targeting this axis boosts anti-tumor immunity.

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