Commentary:The ubiquitin-proteasome system in the tumor immunemicroenvironment: a key force in combination therapy

Xin Shi ^1* Lu Zhang ¹ Liping Jia ¹ Wenxiu Yuan ¹ Linhan Wang ²

• ¹ Qingdao Municipal Hospital, Qingdao, China
• ² Imperial College London, London, England, United Kingdom

The review by Yongmei Wang et al., "The ubiquitin-proteasome system in the tumor immune microenvironment: a key force in combination therapy," provides a comprehensive analysis of the UPS's role in the TIME, highlighting its potential as a therapeutic target in immunotherapy [1]. Despite this, the review could benefit from a more detailed discussion on the UPS's impact on the transcription factor FOXP3, the regulation of immune cell function by E3 ubiquitin-protein ligases, and the emerging role of Proteolysis Targeting Chimeras (PROTACs) in modulating E3 ligase activity. FOXP3 stability and function [2].The activity and expression of FOXP3 are regulated by various E3 ubiquitin-protein ligases, such as CBLB and STUB1. These These mechanisms should be elaborated upon to provide a comprehensive understanding of how the UPS influences Treg biology [7].Identifying E3 ligases and their mechanisms in cancers like breast cancer can provide new therapeutic targets for patients, especially those with advanced, recurrent, and metastatic disease [8].In terms of drug development, there has been significant progress in targeting the UPS for cancer therapy. Proteasome inhibitors, such as bortezomib, have been approved for the treatment of multiple myeloma and mantle cell lymphoma [9]. Additionally, the development of deubiquitinating enzyme (DUB) inhibitors is an emerging area of research, with several compounds entering preclinical and clinical trials [10]. For instance, the USP7 inhibitor P5091 has shown promise in the treatment of multiple myeloma by promoting the ubiquitination and degradation of MDM2, thereby activating the p53 pathway [11].The review also provides a thorough summary of the current research on the potential of E3 ligases as drug targets. E3 ligases, such as SPOP and FBXO22, have been shown to ubiquitinate and degrade PD -L1, suggesting that their inhibition could enhance anti-tumor immune responses [11]. Furthermore, the role of neddylation in regulating the activity of CRL E3 ligase complexes has been highlighted, with the potential for neddylation inhibitors to disrupt TAM recruitment and tumor immune evasion .Proteolysis Targeting Chimeras (PROTACs) i s a promising therapeutic strategy in immunotherapy [12], with one end targeting the protein of interest (POI) and the other end binding to a ubiquitin E3 ligase. By