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DJ-1 inhibition reshapes tumor microenvironment and potentiates immune checkpoint inhibitors

Haiying Zhu1,2, Yushen Lin1,3, Li Jiang1,3

  • 1Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.

Science Advances
|April 8, 2026
PubMed

Insights

DJ-1 negatively regulates T cells, hindering cancer immunotherapy. Its inhibition boosts antitumor immunity and enhances checkpoint blockade efficacy, offering a new strategy for refractory cancer patients.

Area of Science:

  • Immunology
  • Oncology
  • Molecular Biology

Background:

  • Immune checkpoint inhibitors (ICIs) show promise in cancer treatment but benefit only a subset of patients.
  • Developing strategies to sensitize resistant tumors to ICIs is a critical unmet clinical need.
  • DJ-1 has been identified as a novel negative regulator of T cell activity.

Purpose of the Study:

  • To investigate the role of DJ-1 in regulating T cell-mediated antitumor immunity.
  • To explore DJ-1 as a potential target for overcoming resistance to immune checkpoint blockade therapy.
  • To evaluate the efficacy of DJ-1 inhibition in combination with PD-1 and TIM-3 blockade in preclinical cancer models.

Main Methods:

  • Utilized DJ-1 knockout murine cancer models.
  • Performed single-cell sequencing on tumor-infiltrating CD45+ cells.
  • Investigated the effects of DJ-1 deficiency on macrophage reprogramming and T cell activation.
  • Assessed the impact of pharmacological DJ-1 inhibition (disulfiram) on combination therapy efficacy.

Main Results:

  • DJ-1 knockout significantly enhanced antitumor immunity and potentiated PD-1 and TIM-3 blockade in cancer models.
  • DJ-1 deficiency reprogrammed macrophages, leading to indirect T cell activation.
  • Loss of DJ-1 increased reactive oxygen species (ROS) in macrophages, activating NF-κB/STAT3 signaling.
  • Macrophage reprogramming promoted differentiation into immune-stimulatory Cxcl9+ phenotypes and reduced immune-suppressive Spp1+ macrophages.
  • Pharmacological inhibition of DJ-1 with disulfiram markedly improved the antitumor efficacy of PD-1 blockade.

Conclusions:

  • DJ-1 acts as a negative regulator of T cell-mediated antitumor immunity.
  • DJ-1 inhibition, through genetic or pharmacological means, can overcome resistance to immune checkpoint inhibitors.
  • DJ-1 is a promising therapeutic target for optimizing combination immunotherapies in refractory cancers.

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