A new review published in Genes & Diseases explores the pivotal role of the ubiquitin-proteasome system (UPS) in regulating the tumor microenvironment (TME) and driving cancer progression . The study provides novel insights into how ubiquitination and deubiquitination impact tumor cells, immune responses, and potential therapeutic strategies for cancer treatment.
The tumor microenvironment is a complex ecosystem of tumor cells, immune cells, and non-cellular components, creating a dynamic interplay that influences cancer development. The study highlights that ubiquitination , a key post-translational protein modification process, is essential for maintaining protein stability and regulating various cellular processes such as cell growth, DNA replication, immune responses, and energy metabolism .
One of the key findings of this review is how the UPS system controls tumor cell proliferation, immune evasion, and metastasis . Multiple E3 ubiquitin ligases and deubiquitinating enzymes (DUBs) that regulate essential cancer-related proteins were identified. For instance, the study outlines the role of MDM2 , an E3 ubiquitin ligase that targets p53 , a well-known tumor suppressor protein. Dysregulation of MDM2 leads to uncontrolled tumor growth , making it a promising target for anti-cancer therapy.
Furthermore, the study delves into the UPS’s impact on immune cells in the TME. Ubiquitination modifications can either promote or suppress immune responses , directly affecting cancer immunotherapy outcomes. The review discusses how targeting PD-1/PD-L1 ubiquitination can enhance T-cell-mediated anti-tumor immunity , a critical finding for improving checkpoint inhibitor therapies.
The authors also explore how the UPS influences non-immune components of the TME, such as tumor-associated fibroblasts (CAFs), macrophages, and the extracellular matrix (ECM) . By regulating protein degradation and signaling pathways, the UPS contributes to angiogenesis, metabolic reprogramming, and tumor cell migration . These findings open new avenues for developing UPS-targeted drugs that could disrupt cancer-supportive environments.
While the therapeutic potential of targeting UPS is immense, this review also acknowledges the challenges of developing effective inhibitors . Existing UPS-targeted drugs, such as proteasome inhibitors (bortezomib, carfilzomib) , have shown clinical success in treating multiple myeloma. However, new strategies, including PROTAC , aim to enhance specificity and reduce toxicity in solid tumors.
This study underscores the UPS as a critical regulator of cancer progression and a promising therapeutic target . Future research will focus on developing selective inhibitors and combination therapies to improve cancer treatment outcomes.
Reference
Yulan Huang, Yuan Gao, Zhenghong Lin, Hongming Miao, Involvement of the ubiquitin-proteasome system in the regulation of the tumor microenvironment and progression, Genes & Diseases, Volume 12, Issue 2, 2025, 101240.
DOI
https://doi.org/10.1016/j.gendis.2024.101240
Journal
Genes & Diseases
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