Proteasome: Role in T Cell Function Regulation

TL;DR

This paper reviews how the proteasome influences T cell function and how understanding this could improve cancer treatments.

Contribution

The paper highlights novel roles of the proteasome in T cell regulation and proposes new strategies for proteasome inhibitor use in immunotherapy.

Findings

Proteasome inhibitors show efficacy in liquid cancers but not solid cancers, possibly due to T cell modulation.

The proteasome affects T cell fate through antigen processing, metabolism, and exhaustion prevention.

New technologies like CRISPR and AI could enhance proteasome inhibitor applications in cancer and autoimmune diseases.

Abstract

The proteasome plays a pivotal role in proteostasis and is deeply involved in various cellular processes. Currently, three proteasome inhibitors have been used for clinical therapies of liquid cancers with favorable efficacy, however they fail to achieve ideal efficiency in clinical trials for solid cancers without a clear clue. Recent studies have unveiled that beyond its canonical role in ubiquitin-mediated protein degradation, the proteasome also elicits a multifaceted influence on T cell fate, steering it through antigen processing, metabolic reprogramming, and the prevention of exhaustion. The proteasome inhibitors may affect tumor progression through their critical role in modulating T cell-mediated antitumor immunity, an understanding of which may solve the mystery underlying the poor efficacy of the proteasome inhibitors for solid cancers and unlock novel strategies for precision immunotherapy. This review will summarize the current knowledge of how proteasome activity weaves its threads through thymic selection, T cell aging, activation, differentiation, and immune evasion. Moreover, we will explore how cutting-edge technologies-CRISPR editing, single-cell proteomics, and AI-driven drug design can expand the application of the proteasome inhibitors in the treatment of cancer and autoimmune diseases.

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