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Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the daughter...

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Enhancement of Apoptotic and Autophagic Induction by a Novel Synthetic C-1 Analogue of 7-deoxypancratistatin in Human Breast Adenocarcinoma and Neuroblastoma Cells with Tamoxifen
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Inhibiting PPM1D Perturbs Mitochondrial Integrity to Stimulate cGAS-STING Signaling and Antitumor Immunity.

Liang Zhang1, Xiang Zheng2, Haotian Fu2

  • 1Second Affiliated Hospital of Zhejiang University Hangzhou, Zhejiang China.

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|June 30, 2026
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Targeting PPM1D overcomes resistance to immune checkpoint blockade (ICB) in hepatocellular carcinoma (HCC). Inhibiting PPM1D enhances CD8+ T-cell activity, improving immunotherapy effectiveness for HCC patients.

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Area of Science:

  • Immunology
  • Oncology
  • Molecular Biology

Background:

  • Immune checkpoint blockade (ICB) is a key therapy for hepatocellular carcinoma (HCC).
  • Resistance to ICB therapy poses a significant clinical challenge in HCC treatment.
  • Identifying novel targets to overcome this resistance is crucial for improving patient outcomes.

Purpose of the Study:

  • To identify novel molecular drivers of immunotherapy resistance in HCC.
  • To investigate the role of PPM1D in HCC progression and response to ICB.
  • To explore PPM1D as a potential therapeutic target for enhancing HCC immunotherapy.

Main Methods:

  • Analysis of PPM1D expression in HCC tumor tissues.
  • Investigating the regulation of PPM1D by TNFα-NF-κB signaling in response to CD8+ T cells.
  • Utilizing genetic and pharmacological inhibition of PPM1D in preclinical HCC models.
  • Elucidating the mechanism of PPM1D action on mitochondrial homeostasis and cGAS-STING-IFN pathway.
  • Assessing the synergistic effect of PPM1D inhibition with PD-1 blockade.

Main Results:

  • PPM1D expression is significantly upregulated in HCC tissues and linked to immunotherapy resistance.
  • Tumor cells increase PPM1D expression upon CD8+ T cell activation via TNFα-NF-κB.
  • PPM1D inhibition enhances CD8+ T cell cytotoxicity and suppresses HCC progression.
  • PPM1D dephosphorylates VDAC2, maintaining mitochondrial homeostasis and suppressing cGAS-STING-IFN signaling.
  • Inhibition of PPM1D synergizes with PD-1 blockade in preclinical HCC models with low toxicity.

Conclusions:

  • PPM1D is a critical driver of immunotherapy resistance in hepatocellular carcinoma.
  • Targeting PPM1D enhances anti-tumor immunity by improving CD8+ T cell function.
  • PPM1D inhibition represents a promising strategy to improve the efficacy of ICB in HCC.