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Augment proteasome inhibitor efficacy activates CD8+ T cell-mediated antitumor immunity in breast cancer

Dongyang Tang1, Shiqi Lin1, Jingbo Zhou2

  • 1Cancer Center, Faculty of Health Sciences, University of Macau, Macau SAR, China; Center for Precision Medicine Research and Training, Faculty of Health Sciences, University of Macau, Macau SAR, China.

Cell Reports. Medicine
|July 3, 2025
PubMed

Insights

Ammonium tetrathiomolybdate (TM) and AMD3100 enhance proteasome inhibitor effectiveness against solid tumors. These drugs activate the AMPK pathway, reduce proteasome activity, and boost CD8+ T cell responses for improved cancer therapy.

Area of Science:

  • Oncology
  • Immunology
  • Pharmacology

Background:

  • Proteasome inhibitors show limited efficacy in solid tumors.
  • Novel therapeutic strategies are needed to improve solid tumor treatment.
  • Drug combinations offer a promising approach to overcome resistance.

Purpose of the Study:

  • To investigate the synergistic effects of ammonium tetrathiomolybdate (TM) and AMD3100 with proteasome inhibitors in solid tumors.
  • To elucidate the underlying molecular mechanisms of drug sensitization.
  • To evaluate the in vivo efficacy and immune-modulatory effects of these combinations.

Main Methods:

  • Utilized solid cancer cell lines for in vitro drug screening.
  • Investigated proteasome activity and protein levels (PSMB5).
  • Analyzed the AMP-activated protein kinase (AMPK) and STAT3 phosphorylation pathways.
  • Conducted in vivo studies using mouse models to assess tumor growth and immune cell responses (CD8+ T cells).

Main Results:

  • TM and AMD3100 sensitized solid cancer cells to proteasome inhibitors by reducing PSMB5 protein levels via AMPK activation.
  • The drug combinations inhibited STAT3 phosphorylation, a key signaling pathway in cancer.
  • In vivo, combinations of bortezomib with TM or AMD3100 significantly retarded tumor growth.
  • These combinations enhanced CD8+ T cell-mediated anti-tumor immunity by increasing antigen presentation and CCL5 production.

Conclusions:

  • Ammonium tetrathiomolybdate (TM) and AMD3100 are effective sensitizers for proteasome inhibitor therapy in solid tumors.
  • The mechanism involves AMPK pathway activation, leading to reduced proteasome activity and enhanced anti-tumor T cell responses.
  • These findings support the development of combination therapies involving proteasome inhibitors, TM, and AMD3100 for improved breast cancer treatment, dependent on an intact immune system.
Keywords:
CCL5antigen presentationbreast cancerimmunotherapyproteasome inhibitor

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