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Related Concept Videos

Tumor Immunotherapy01:27

Tumor Immunotherapy

Immunotherapy is a treatment that boosts or manipulates the immune system to fight diseases, including cancer. For instance, by stimulating an immune response through vaccinations against viruses that cause cancers, like hepatitis B virus and human papillomavirus, these diseases can be prevented. Nonetheless, some cancer cells can avoid the immune system due to their rapid mutation and division. The immune response to many cancers involves three phases: elimination, equilibrium, and escape.
Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against specific...

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Related Experiment Video

Updated: Jul 15, 2026

Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
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Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs

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Repurposed ethoxzolamide reprograms antitumor immunity through β-TrCP-dependent PD-L1 ubiquitination.

Xuwen Lin1, Qun Wang2, Mengting Xu2

  • 1Department of Respiratory and Critical Care, Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing 100053, China.

Cell Reports. Medicine
|July 13, 2026
PubMed
Summary

Ethoxzolamide (EZA) reduces PD-L1 protein levels by promoting its degradation. This restores anti-tumor T cell activity and overcomes resistance to immunotherapy, offering new therapeutic potential.

Keywords:
cancer immunotherapyethoxzolamideprogrammed death-ligand 1ubiquitination and degradationβ-transducin repeat-containing protein

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Area of Science:

  • Oncology
  • Immunology
  • Pharmacology

Background:

  • Programmed cell death protein 1 (PD-1)/PD-L1 blockade shows clinical efficacy in solid tumors.
  • Tumor resistance to PD-1/PD-L1 blockade can be mediated by PD-L1 protein stabilization.
  • Alternative strategies are needed to overcome resistance and enhance immunotherapy efficacy.

Purpose of the Study:

  • To identify novel negative regulators of PD-L1.
  • To investigate the mechanism of action of ethoxzolamide (EZA) on PD-L1.
  • To evaluate the therapeutic potential of EZA in preclinical cancer models and clinical data.

Main Methods:

  • Identified ethoxzolamide (EZA) as a carbonic anhydrase inhibitor that negatively regulates PD-L1.
  • Investigated EZA's binding to the E3 ubiquitin ligase β-TrCP and its effect on PD-L1 polyubiquitination and degradation.
  • Assessed EZA's impact on tumor cell PD-L1 expression, T cell-mediated cytotoxicity in vitro, and the tumor immune microenvironment in vivo.
  • Analyzed EZA's synergy with anti-CTLA-4 therapy and correlated PD-L1/β-TrCP expression with patient response in non-small cell lung cancer (NSCLC).

Main Results:

  • EZA binds to β-TrCP, inducing K48-linked polyubiquitination and proteasomal degradation of PD-L1.
  • EZA downregulates tumor cell PD-L1, restoring T cell-mediated cytotoxicity.
  • EZA reprograms the tumor immune microenvironment, reducing myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) while enhancing cytotoxic responses in murine models.
  • EZA synergizes with anti-CTLA-4 therapy to overcome treatment resistance.
  • High PD-L1 and low β-TrCP expression correlate with superior response in NSCLC patients treated with neoadjuvant immunotherapy.

Conclusions:

  • Ethoxzolamide (EZA) functions as a novel negative regulator of PD-L1 through the β-TrCP/proteasome pathway.
  • EZA demonstrates significant antitumor activity by restoring anti-tumor immunity and overcoming immunotherapy resistance.
  • The PD-L1/β-TrCP axis represents a potential therapeutic target for enhancing cancer immunotherapy, particularly in NSCLC.