USP39 at the crossroads of cancer immunity - regulating immune evasion and immunotherapy response through RNA splicing and ubiquitin signaling

Sep 23, 2026

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Ubiquitin-specific protease 39 (USP39), a key deubiquitinating enzyme, removes ubiquitin from substrates and thereby modulates diverse signaling and transcriptional programs. This review summarizes USP39 structural domains and biological functions, highlighting roles in DNA damage repair and RNA splicing, and extending to epithelial maintenance, resistance to viral infection, vascular remodeling, and disease states. It further analyzes aberrant USP39 expression in cancers, effects on cancer markers and tumor progression, and the rationale for developing USP39 inhibitors. Targeting USP39 may also counter checkpoint-inhibitor resistance to improve cancer immunotherapy efficacy.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages17

Reading Time43 min

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Introduction

Ubiquitination and deubiquitylation background

USP39 structural domains and functions

USP39 roles in DNA damage repair and RNA splicing

USP39 in epithelial morphology, viral infection resistance, and vascular remodeling

USP39 in cancer: expression, markers, and tumor progression

Therapeutic targeting of USP39 and immunotherapy response

TYPE Review PUBLISHED 08 September 2025 DOI 10.3389/fimmu.2025.1665775 OPEN ACCESS EDITED BY Shangke Huang, Southwest Medical University, China REVIEWED BY Houjuan Zhu, Institute of Materials Research and Engineering (ASTAR), Singapore Jinxiang Wang, Sun Yat-sen University, China *CORRESPONDENCE Yanlong Shi [vvshiyanlong@qq.com](vvshiyanlong@qq.com)[ ](vvshiyanlong@qq.com)Zhenyu He [hezhenyu1968@163.com](hezhenyu1968@163.com) †These authors have contributed equally to this work RECEIVED 14 July 2025 ACCEPTED 25 August 2025 PUBLISHED 08 September 2025 CITATION Zhou F, Li X, Sun Y, Wang Y, Niu K, Gao X, Zhang J, Chen T, Li Y, Zhao W, Mao B, Xu Q, Shi Y and He Z (2025) USP39 at the crossroads of cancer immunity: regulating immune evasion and immunotherapy response through RNA splicing and ubiquitin signaling. Front. Immunol. 16:1665775 . doi: 10.3389/fimmu.2025.1665775 COPYRIGHT © 2025 Zhou, Li, Sun, Wang, Niu, Gao, Zhang, Chen, Li, Zhao, Mao, Xu, Shi and He. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. USP39 at the crossroads of cancer immunity: regulating immune evasion and immunotherapy response through RNA splicing and ubiquitin signaling Feilong Zhou 1†, Xinhao Li 1†, Yanmei Sun 1†, Yizhu Wang 1†, Kaiyi Niu 1, Xin Gao 1, Jiaqi Zhang 1, Tianyi Chen 1, Yunxin Li 1, Weijie Zhao 1, Binyue Mao 2, Qiyang Xu 3, Yanlong Shi 4* and Zhenyu He 1* 1General Surgery Department, The Second Afﬁliated Hospital of Nanjing Medical University, Nanjing, China, 2 Department of Dermatology, The First Afﬁliated Hospital of Xi ’an Jiaotong University, Xi’an, China, 3General Surgery Department, Fuyang Fifth People’s Hospital, Fuyang, China, 4General Surgery Department, Fuyang Hospital of Anhui Medical University, Fuyang, China Deubiquitinating enzymes (DUBs) are responsible for the removal of ubiquitin from substrates, thereby antagonizing ubiquitination and regulating a multitude of biological pathways including cell cycle progression, signal transduction, and transcriptional regulation. Ubiquitin Speciﬁc Protease-39 (USP39), a pivotal member of the ubiquitin-speciﬁc protease family, is intricately linked to innumerable pathophysiological processes. In this review, we ﬁrst provide an overview of the speciﬁc structural domains and biological functions of USP39, with a particular focus on its role in DNA damage repair and RNA splicing processes. Then, we delineate the function of USP39 in maintaining epithelial morphology, resistance to viral infection, vascular remodeling, and pathological states. Moreover, we particularly focus on the aberrant expression of USP39 in various cancers and its effect on cancer markers, as well as on the regulatory role of USP39 in tumor progression. In conclusion, a comprehensive analysis of the structural domains and functional properties of USP39, a detailed investigation into its interaction mechanisms with diverse substrates, and the accelerated development of related inhibitors will provide a novel theoretical foundation for the treatment of numerous diseases, including tumors. Importantly, targeting USP39 may overcome resistance to checkpoint inhibitors, offering a promising approach to enhance cancer immunotherapy efﬁcacy. KEYWORDS USP39, deubiquitylation, structure, DNA damage repair, RNA splicing, regulation cancers, immunotherapy Frontiers in Immunology 01 [frontiersin.org](frontiersin.org) Zhou et al. 10.3389/fimmu.2025.1665775 GRAPHICAL ABSTRACT This review provides a comprehensive overview of USP39 ’s structure, physiological function, an

FAQs

What is USP39, and what biological processes does it influence?

USP39 is a member of the ubiquitin-specific protease family that removes ubiquitin from substrates. It influences multiple pathways including DNA damage repair, RNA splicing, and broader regulation of disease-relevant cellular functions.

How does USP39 relate to cancer immunity and immunotherapy response?

The review emphasizes USP39’s involvement in regulating immune evasion and its impact on immunotherapy outcomes. Targeting USP39 is proposed to help overcome resistance to checkpoint inhibitors and enhance immunotherapy efficacy.

Which areas does the review cover regarding USP39 mechanisms and therapeutic potential?

It covers USP39 structural domains, functional roles across multiple biological contexts, interactions with diverse substrates, and the accelerated development of related USP39 inhibitors to support treatment of tumors and other diseases.

Sep 23, 2026

Uploaded by Elsa