Proteasome: Role in T Cell Function Regulation

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.