Dissecting the dual role of OTU family proteins in tumor progression and immune escape

Abstract

As a core mechanism regulating intracellular protein homeostasis, the dynamic equilibrium between ubiquitination and deubiquitination profoundly impacts the functionality and fate of target proteins. The Ovarian tumor domain (OTU) family, a vital subclass of deubiquitinating enzymes, comprises 16 members that mediate ubiquitin binding and hydrolysis through their characteristic OTU domain. Recent years have witnessed growing interest in OTU family members in oncology and immunology research. This review comprehensively elucidates the core mechanisms by which OTU members regulate tumor-associated signaling networks via substrate-specific deubiquitination. On one hand, they directly govern tumor cell proliferation, metastasis, and apoptosis by modulating the stability of key substrates. On the other hand, they orchestrate tumor progression through dynamic regulation of inflammatory intensity, immune response duration, and immune evasion mechanisms within the tumor microenvironment (TME), thereby constructing a multidimensional regulatory network in tumor development. These findings not only unveil the pivotal role of OTU family members in tumorigenesis and immune modulation but also establish a theoretical foundation for developing novel anti-tumor therapeutics targeting deubiquitination processes. Notably, OTUs emerge as high-potential therapeutic targets with high translational relevance for refining precision-guided tumor-immunotherapy integration strategies.

Keywords: OTU family; deubiquitinating enzymes; immune regulation; tumorigenesis; ubiquitination-deubiquitination balance.

Figure 1

Diagram of ubiquitination and deubiquitination mechanisms.

Figure 2

Structural characteristics of OTU family members. OTU domain, ovarian tumor domain; UIM, ubiquitin-interacting motif; UBX-like, ubiquitin regulatory X-like; UBA-like, ubiquitin-associated-like; NLS, nuclear localization signals; ANK, ankyrin motif; PIM, PUB interacting motif; LDB, linear diubiquitin binding; RMB, required for membrane binding.

Figure 3

Role of OTU family members in tumor progression. The red font represents OTUs exerting an oncogenic effect in specific cancers, while the green font is for an inhibitory effect.

Figure 4

Relationship of OTU family members to tumor characteristics. (A) Dual role of OTUs in specific cancers. (B) OTUs maintain cancer stem cell-like properties. (C) OTUs regulate tumor ferroptosis. (D) OTUs participate in DNA repair. (E, F) OTUs are involved in tumor chemotherapy and radiotherapy. The red font represents OTUs exerting an oncogenic effect in specific cancers, while the green font is for an inhibitory effect.

Figure 5

Differential expression and prognostic value of OTU family members in cancer and normal tissues using the TCGA pan-cancer cohort.

Figure 6

Functions of OTUs in immunity. OTUs are involved in innate and adaptive immune responses, inflammation and autoimmunity, and anti-viral and anti-tumor immune responses.