USP7: The Double-Edged Deubiquitinase That Tumors Cannot Live Without

Inside every human cell, an elaborate recycling system works around the clock, tagging worn-out or misfolded proteins with a small molecular label called ubiquitin and shipping them off to the proteasome for destruction. But the system also runs in reverse. A family of enzymes known as deubiquitinating enzymes, or DUBs, can snip those ubiquitin tags back off, rescuing proteins from degradation and extending their working lives. A new review published in Cancer Cell International spotlights one of the most consequential members of this family, ubiquitin-specific protease 7, or USP7, and maps out why this single enzyme has become one of the most closely watched targets in contemporary cancer drug discovery. Written by Shan Huang, Nuerbiye Abudurexiti, Min Cheng, Yinan Huang and Song Zheng of Zhejiang Chinese Medical University and affiliated hospitals in Hangzhou, the review synthesizes what is known about USP7’s role in tumor progression and the stubborn obstacles that stand between laboratory inhibitors and clinical use.

USP7, historically known as HAUSP because it was first identified through its interaction with the herpes simplex virus type 1 protein ICP0, is a cysteine protease whose catalytic activity is modulated by a large N-terminal TRAF domain. This domain is the molecular handshake that allows USP7 to recognize a remarkably diverse cast of substrate proteins. By removing ubiquitin marks from these partners, USP7 can stabilize them, alter their localization, or change their activity, and in doing so it touches nearly every major process a cancer cell cares about: DNA damage repair, epigenetic programming, cell cycle control, apoptosis, metabolism and immune evasion. The stakes are high well beyond oncology. The review emphasizes that USP7 is indispensable for normal physiology, since mice engineered to lack the enzyme from conception die during early embryonic development, a finding that underscores its essential role in maintaining genome stability and developmental homeostasis.

The most famous thread in the USP7 story runs through the tumor suppressor p53, the guardian of the genome whose loss or mutation underpins roughly half of all human cancers. Under ordinary, unstressed conditions in tumors that still carry a functional, wild-type copy of the p53 gene, USP7 tends to act as a quiet accomplice of cancer. Its preferred client in this setting is MDM2, the E3 ubiquitin ligase whose entire job is to attach ubiquitin to p53 and drag it to the proteasome. By keeping MDM2 stable and active, USP7 accelerates p53 turnover and keeps the tumor suppressor’s alarm system dialed down, allowing malignant cells to proliferate unchecked. In this scenario, inhibiting USP7 would seem like an obvious win: MDM2 degrades, p53 accumulates, and the cell either arrests its cell cycle or initiates apoptosis.

Yet the biology refuses to stay simple. The review details how, under conditions of DNA damage stress, USP7 can flip sides entirely. When the genome is injured, USP7 can directly deubiquitinate p53 itself, stabilizing the tumor suppressor and helping it trigger the transcriptional programs that halt division and repair the damage. This context-dependent duality, the authors argue, is the central paradox that has complicated every attempt to drug the enzyme. In a p53 wild-type tumor, a USP7 inhibitor might unleash p53 and kill the cancer, but in normal tissues exposed to genotoxic stress from chemotherapy or radiation, the same inhibition could blunt a protective p53 response. The enzyme is, in the review’s framing, a double-edged sword whose effect depends on which substrates are present, what stress the cell is under, and what the p53 status happens to be.

In tumors where p53 is mutated or deleted altogether, the calculus changes again. With the p53 checkpoint gone, USP7’s oncogenic contributions come almost entirely from its other clients, and the review catalogs an impressive roster. USP7 stabilizes the transcription factor Myc, a master driver of proliferation whose overexpression marks many aggressive malignancies. It stabilizes NF-κB components, fueling inflammatory signaling and survival. It protects EZH2, the catalytic engine of the Polycomb Repressive Complex 2, which deposits the repressive H3K27me3 histone mark and silences tumor suppressor programs. Through these and other substrates, USP7 supports metabolic reprogramming, including the glycolytic shift mediated by proteins such as SLC2A1, hexokinase 2 and lactate dehydrogenase A, and it helps cancer cells dodge immune surveillance, in part through effects on PD-L1 and other immune-modulatory molecules.

The enzyme’s reach extends deep into the DNA damage response, a dimension that carries direct therapeutic implications. USP7 interacts with and stabilizes components of the checkpoint machinery, including the MRN complex mediator MDC1, the p53-binding protein 53BP1, checkpoint kinase 1 and its partner claspin, as well as repair factors such as CtIP and the nuclease SAMHD1. By keeping these proteins abundant, USP7 helps cancer cells survive the constant DNA insults of rapid division and, more troublingly, helps them repair the damage inflicted by genotoxic chemotherapy and radiation. This has prompted interest in combining USP7 inhibitors with DNA-damaging agents or with PARP inhibitors, on the logic that disabling USP7 would leave tumors with fewer tools to patch their broken genomes. The review also connects USP7 to epigenetic regulation beyond EZH2, noting interactions with LSD1, HDAC1 and the DNA methyltransferases DNMT1, DNMT3A and DNMT3B, positioning the enzyme as a hub where chromatin state and genome maintenance converge.

The clinical evidence base is growing across tumor types. The review highlights roles for USP7 in T-cell acute lymphoblastic leukemia, where it supports NOTCH1-driven signaling, and in acute myeloid leukemia, as well as in activated B-cell-like diffuse large B-cell lymphoma, where USP7 inhibition has been explored in combination with B-cell receptor pathway blockade and glucocorticoids such as dexamethasone. In solid tumors, USP7 has been implicated in pancreatic ductal adenocarcinoma through interactions with IGF2BP2 and platelet-derived growth factor signaling involving cancer-associated fibroblasts, in HER2-positive breast cancer, in non-small cell lung cancer, and in hepatobiliary and other gastrointestinal malignancies. Natural products have also entered the picture, with the toad venom-derived compound cinobufagin reported to act through USP7 in preclinical models. Each of these associations reinforces the same conclusion: USP7 sits at a bottleneck through which many oncogenic signals pass.

Drug developers have responded with a wave of small-molecule inhibitors, and the review provides a technical tour of how they were built. Early compounds were identified using activity-based assays with artificial substrates such as ubiquitin-7-amino-4-methylcoumarin, and their binding was characterized by techniques including surface plasmon resonance, isothermal titration calorimetry and nuclear magnetic resonance spectroscopy. Structure-based drug design against the catalytic domain has produced increasingly potent inhibitors, some with half-maximal inhibitory concentrations in the low nanomolar range. Yet the review is candid about why none has yet transformed oncology practice. On-target toxicity remains a serious concern, a direct consequence of USP7’s essential normal functions. Selectivity is insufficient, because the catalytic domains of the more than fifty human ubiquitin-specific proteases are architecturally similar, raising the specter of off-target effects on related DUBs. Pharmacokinetic properties have often been poor, and efficacy has proved stubbornly context-dependent, working in some cellular settings and failing in others for reasons that are only partly understood.

The path forward, the authors argue, requires more than simply building stronger inhibitors. They call for the development of highly selective molecules, ideally ones that exploit the TRAF domain and substrate-recognition surfaces rather than the conserved catalytic core, which could discriminate USP7 from its relatives. They emphasize the need to elucidate context-specific regulatory networks so that clinicians can predict which patients will benefit, and they advocate the search for predictive biomarkers, with p53 status, EZH2 dependence and Myc activation emerging as obvious candidates for stratification. Combination regimens, pairing USP7 inhibitors with immune checkpoint blockade, epigenetic drugs, DNA damage response inhibitors or conventional chemotherapy, are highlighted as the most promising route to overcoming the redundancy that cancer cells exploit when a single pathway is blocked.

What makes the USP7 story resonate beyond the specialist literature is what it reveals about modern cancer biology as a whole. The ubiquitin-proteasome system, once viewed mainly as cellular housekeeping, has turned out to be a dense regulatory network in which a single deubiquitinase can simultaneously tune tumor suppression, oncogene activation, genome repair and immune recognition. USP7 embodies the promise and the peril of targeting such hubs: it is druggable, it is implicated across an extraordinary range of malignancies, and inhibiting it could reverse chemoresistance in ways that conventional targeted agents cannot. But its essential role in embryonic development and genome stability means that any clinical strategy must walk a narrow line between poisoning the tumor and harming the patient. The Hangzhou team’s synthesis makes clear that the next phase of USP7 research will be less about proving the enzyme matters and more about learning, with molecular precision, when and how to pull the trigger.

Subject of Research: The role of the deubiquitinase USP7 in tumor progression and the development of USP7-targeted cancer therapies

Article Title: Ubiquitin-specific protease 7 (USP7): a key deubiquitinase governing tumor progression and therapeutic vulnerabilities

Article References: Ubiquitin-specific protease 7 (USP7): a key deubiquitinase governing tumor progression and therapeutic vulnerabilities. (n.d.). https://doi.org/10.1186/s12935-026-04483-0

Image Credits: AI Generated

DOI: 10.1186/s12935-026-04483-0

Keywords: USP7, deubiquitinase, p53, MDM2, ubiquitin-proteasome system, small-molecule inhibitors, targeted therapy, DNA damage response, EZH2, Myc, cancer drug discovery, combination therapy