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

Panpan Dai1, Yishuang Sun1,2, Zhengrong Huang3

  • 1Department 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.

Nature Communications
|May 16, 2025
PubMed

Insights

Inhibiting USP2 reduces CD47, enhancing cancer cell clearance and anti-PD-1 immunotherapy. This approach reprograms the tumor microenvironment, improving treatment response in preclinical models and predicting clinical outcomes.

Area of Science:

  • Immunology
  • Oncology
  • Molecular Biology

Background:

  • The CD47/SIRPα pathway is a critical 'don't eat me' signal that protects tumor cells from phagocytosis.
  • While CD47-blocking antibodies show promise, clinical efficacy has been limited, necessitating exploration of regulatory mechanisms for improved therapies.

Purpose of the Study:

  • To investigate the role of USP2 in regulating CD47 stability and its impact on the tumor microenvironment (TME) and anti-PD-1 immunotherapy.
  • To explore USP2 inhibition as a strategy to enhance anti-tumor immunity and phagocytic clearance of cancer cells.

Main Methods:

  • Investigated the interaction between USP2 and CD47 using biochemical assays.
  • Utilized USP2 inhibitors (e.g., ML364) in preclinical cancer models.
  • Performed single-cell RNA sequencing to analyze TME reprogramming.
  • Correlated USP2 expression with anti-PD-1 treatment response in clinical data.

Main Results:

  • USP2 directly interacts with CD47, stabilizing it via deubiquitination.
  • USP2 inhibition leads to CD47 degradation, enhancing macrophage phagocytosis of tumor cells.
  • USP2 inhibition reprograms the TME, increasing M1 macrophages and CD8+ T cells while decreasing M2 macrophages.
  • Combination therapy with ML364 and anti-PD-1 reduced tumor burden in mouse models.
  • Low USP2 expression correlated with a better response to anti-PD-1 therapy in cancer patients.

Conclusions:

  • USP2 is a key regulator of CD47 stability and function.
  • Targeting the USP2/CD47 axis enhances anti-tumor immunity and phagocytosis.
  • USP2 inhibition represents a promising strategy to improve the efficacy of anti-PD-1 immunotherapy.

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