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Updated: Jul 29, 2025

Fluorescence-based Monitoring of PAD4 Activity via a Pro-fluorescence Substrate Analog
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The proteasome regulator PSME4 modulates proteasome activity and antigen diversity to abrogate antitumor immunity in

Aaron Javitt1, Merav D Shmueli2, Matthias P Kramer1

  • 1Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel.

Nature Cancer
|May 22, 2023
PubMed

Insights

Proteasome complex changes in cancer impact immune response and immunotherapy effectiveness. Upregulation of PSME4 in tumors is linked to reduced antigen diversity and poor treatment outcomes.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Immunotherapy has transformed cancer treatment but resistance mechanisms are not fully understood.
  • Cellular proteasomes influence antitumor immunity through antigen processing and immune cell regulation.
  • The role of proteasome complex heterogeneity in cancer progression and immunotherapy response is largely unexplored.

Purpose of the Study:

  • To investigate the impact of proteasome complex heterogeneity on tumor progression and immunotherapy response.
  • To profile the degradation landscape in non-small-cell lung carcinoma (NSCLC) patient samples.
  • To examine the function of proteasome regulators in the tumor microenvironment.

Main Methods:

  • Profiling the degradation landscape of patient-derived NSCLC samples.
  • Analyzing proteasome complex composition across different cancer types.
  • Assessing the correlation between proteasome regulators and immunotherapy response.

Main Results:

  • Proteasome complex composition significantly varies across cancers, affecting tumor-immune interactions.
  • The proteasome regulator PSME4 is upregulated in tumors.
  • PSME4 upregulation alters proteasome activity, reduces presented antigenic diversity, and correlates with lack of immunotherapy response.

Conclusions:

  • Proteasome composition heterogeneity is a critical factor influencing tumor progression and immunotherapy outcomes.
  • PSME4 is a potential biomarker for predicting immunotherapy response in cancer.
  • Targeting proteasome composition presents a novel strategy for precision oncology and enhancing cancer immunotherapy.

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