GLYCOCINS: The sugar peppered antimicrobials.

Glycosylated bacteriocins, known as glycocins, were first discovered in 2011. These bioactive peptides are produced by bacteria to gain survival advantages. They exhibit diverse types of glycans and demonstrate varied antimicrobial activity. Currently, there are 13 experimentally known glycocins, with over 250 identified in silico across different bacterial phyla. Notably, glycocins are recognized for their glycan-mediated antimicrobial activity, proving effective against drug-resistant and foodborne pathogens. Many glycocins contain rare S-linked glycans. Glycosyltransferases (GTs), responsible for transferring sugar to glycocins and involved in glycocin biosynthesis, often cluster together in the producer's genome. This clustering makes them valuable for custom glycoengineering with diverse substrate specificities. Heterologous expression of glycocins has paved the way for the establishment of microbial factories for glycopeptide and glycoconjugate production across various industries. In this review, we emphasize the primary roles of fully and partially characterized glycocins and their glycosylating enzymes. Additionally, we explore how specific glycan structures facilitate these functions in antibacterial activities. Furthermore, we discuss newer approaches and increasing efforts aimed at exploiting bacterial glycobiology for the development of food preservatives and as replacements or complements to traditional antibiotics, particularly in the face of antibiotic-resistant pathogenic bacteria.

Therapeutic Implications and Regulations of Protein Post-translational Modifications in Parkinsons Disease.

Parkinsons disease (PD) is a neurodegenerative disorder characterized by dopaminergic neuron loss and alpha-synuclein aggregation. This comprehensive review examines the intricate role of post-translational modifications (PTMs) in PD pathogenesis, focusing on DNA methylation, histone modifications, phosphorylation, SUMOylation, and ubiquitination. Targeted PTM modulation, particularly in key proteins like Parkin, DJ1, and PINK1, emerges as a promising therapeutic strategy for mitigating dopaminergic degeneration in PD. Dysregulated PTMs significantly contribute to the accumulation of toxic protein aggregates and dopaminergic neuronal dysfunction observed in PD. Targeting PTMs, including epigenetic strategies, addressing aberrant phosphorylation events, and modulating SUMOylation processes, provides potential avenues for intervention. The ubiquitin-proteasome system, governed by enzymes like Parkin and Nedd4, offers potential targets for clearing misfolded proteins and developing disease-modifying interventions. Compounds like ginkgolic acid, SUMO E1 enzyme inhibitors, and natural compounds like Indole-3-carbinol illustrate the feasibility of modulating PTMs for therapeutic purposes in PD. This review underscores the therapeutic potential of PTM-targeted interventions in modulating PD-related pathways, emphasizing the need for further research in this promising area of Parkinsons disease therapeutics.

Capturing Legionella pneumophila effector enzymes using a ubiquitin derived photo-activatable probe.

Upon infection of host cells the Legionella pneumophila bacterium releases a multitude of effector enzymes into the host's cytoplasm that manipulate cellular host pathways, including the host-ubiquitination pathways. The effectors belonging to the SidE-family are involved in non-canonical phosphoribosyl serine ubiquitination (PR-ubiquitination) of host substrate proteins. This results in the recruitment of ER-remodeling proteins and the formation of a Legionella-containing vacuole which is crucial in the onset of legionnaires disease. PR-ubiquitination is a dynamic process reversed by other Legionella effectors called Dups. During PR-Ubiquitin phosphodiester hydrolysis Dups form a covalent intermediate with the phosphoribosyl ubiquitylated protein using its active site His67 residue. We envisioned that covalent probes to target Legionella effectors could be of value to study these effectors and contribute to deciphering the complex biology of Legionella infection. Hence we effectively installed a photo-activatable pyridinium warhead on the 5'-OH of triazole-linked ribosylated ubiquitin allowing crosslinking of the probe to the catalytic histidine residues in Legionella SidE or Dup enzymes. In vitro tests on recombinantly expressed DupA and SdeAPDE revealed that the probe was able to capture the enzymes covalently upon photo-activation.

Demystifying PTM Identification Using MODplus: Best Practices and Pitfalls.

Tandem mass spectrometry (MS/MS) facilitates the rapid identification of posttranslational modifications (PTMs), which play a pivotal role in regulating numerous biological processes. This chapter explores recent advancements that expand the types of detectable PTMs and enhance the speed of the PTM searches. We also delve into computational challenges associated with searching for a multitude of PTMs simultaneously. The latter section introduces an automated procedure to identify an extensive range of PTMs using MODplus, a free PTM analysis software tool. We guide the reader through the preparation of the modification search, the determination of optional search parameters, the execution of the search, and the analysis of results, exemplified by a case study using specific MS/MS dataset.

Glycation in the cardiomyocyte.

Glycation is a protein post-translational modification that can occur on lysine and arginine residues as a result of a non-enzymatic process known as the Maillard reaction. This modification is irreversible, so the only way it can be removed is by protein degradation and replacement. Small reactive carbonyl species, glyoxal and methylglyoxal, are the primary glycating agents and are elevated in several conditions associated with an increased risk of cardiovascular disease, including diabetes, rheumatoid arthritis, smoking, and aging. Thus, how protein glycation impacts the cardiomyocyte is of particular interest, to both understand how these conditions increase the risk of cardiovascular disease and how glycation might be targeted therapeutically. Glycation can affect the cardiomyocyte through extracellular mechanisms, including RAGE-based signaling, glycation of the extracellular matrix that modifies the mechanical environment, and signaling from the vasculature. Intracellular glycation of the cardiomyocyte can impact calcium handling, protein quality control and cell death pathways, as well as the cytoskeleton, resulting in a blunted contractility. While reducing protein glycation and its impact on the heart has been an active area of drug development, multiple clinical trials have had mixed results and these compounds have not been translated to the clinic-highlighting the challenges of modulating myocyte glycation. Here we will review protein glycation and its effects on the cardiomyocyte, therapeutic attempts to reverse these, and offer insight as to the future of glycation studies and patient treatment.

Predictive modeling for ubiquitin proteins through advanced machine learning technique.

Ubiquitination is an essential post-translational modification mechanism involving the ubiquitin protein's bonding to a substrate protein. It is crucial in a variety of physiological activities including cell survival and differentiation, and innate and adaptive immunity. Any alteration in the ubiquitin system leads to the development of various human diseases. Numerous researches show the highly reversibility and dynamic of ubiquitin system, making the experimental identification quite difficult. To solve this issue, this article develops a model using a machine learning approach, tending to improve the ubiquitin protein prediction precisely. We deeply investigate the ubiquitination data that is proceed through different features extraction methods, followed by the classification. The evaluation and assessment are conducted considering Jackknife tests and 10-fold cross-validation. The proposed method demonstrated the remarkable performance in terms of 100 %, 99.88 %, and 99.84 % accuracy on Dataset-I, Dataset-II, and Dataset-III, respectively. Using Jackknife test, the method achieves 100 %, 99.91 %, and 99.99 % for Dataset-I, Dataset-II and Dataset-III, respectively. This analysis concludes that the proposed method outperformed the state-of-the-arts to identify the ubiquitination sites and helpful in the development of current clinical therapies. The source code and datasets will be made available at Github.

N6-methyladenosine modification and post-translational modification of epithelial-mesenchymal transition in colorectal cancer.

Colorectal cancer is a leading cause of cancer-related mortality worldwide. Traditionally, colorectal cancer has been recognized as a disease caused by genetic mutations. However, recent studies have revealed the significant role of epigenetic alterations in the progression of colorectal cancer. Epithelial-mesenchymal transition, a critical step in cancer cell metastasis, has been found to be closely associated with the tumor microenvironment and immune factors, thereby playing a crucial role in many kinds of biological behaviors of cancers. In this review, we explored the impact of N6-methyladenosine and post-translational modifications (like methylation, acetylation, ubiquitination, SUMOylation, glycosylation, etc.) on the process of epithelial-mesenchymal transition in colorectal cancer and the epigenetic regulation for the transcription factors and pathways correlated to epithelial-mesenchymal transition. Furthermore, we emphasized that the complex regulation of epithelial-mesenchymal transition by epigenetics can provide new strategies for overcoming drug resistance and improving treatment outcomes. This review aims to provide important scientific evidence for the prevention and treatment of colorectal cancer based on epigenetic modifications.

Lactate and lactylation in macrophage metabolic reprogramming: current progress and outstanding issues.

It is commonly known that different macrophage phenotypes play specific roles in different pathophysiological processes. In recent years, many studies have linked the phenotypes of macrophages to their characteristics in different metabolic pathways, suggesting that macrophages can perform different functions through metabolic reprogramming. It is now gradually recognized that lactate, previously overlooked as a byproduct of glycolytic metabolism, acts as a signaling molecule in regulating multiple biological processes, including immunological responses and metabolism. Recently, lactate has been found to mediate epigenetic changes in macrophages through a newfound lactylation modification, thereby regulating their phenotypic transformation. This novel finding highlights the significant role of lactate metabolism in macrophage function. In this review, we summarize the features of relevant metabolic reprogramming in macrophages and the role of lactate metabolism therein. We also review the progress of research on the regulation of macrophage metabolic reprogramming by lactylation through epigenetic mechanisms.

Protein Lactylation Profiles Provide Insights into Molecular Mechanisms Underlying Metabolism in Yak.

Protein lysine lactylation, a recently discovered post-translational modification (PTM), is prevalent across tissues and cells of diverse species, serving as a regulator of glycolytic flux and biological metabolism. The yak (Bos grunniens), a species that has inhabited the Qinghai-Tibetan Plateau for millennia, has evolved intricate adaptive mechanisms to cope with the region's unique geographical and climatic conditions, exhibiting remarkable energy utilization and metabolic efficiency. Nonetheless, the specific landscape of lysine lactylation in yaks remains poorly understood. Herein, we present the first comprehensive lactylome profile of the yak, effectively identifying 421, 308, and 650 lactylated proteins in the heart, muscles, and liver, respectively. These lactylated proteins are involved in glycolysis/gluconeogenesis, the tricarboxylic acid cycle, oxidative phosphorylation, and metabolic process encompassing carbohydrates, lipids, and proteins during both anaerobic and aerobic glucose bio-oxidation, implying their crucial role in material and energy metabolism, as well as in maintaining homeostasis in yaks.

The Plant PTM Viewer 2.0: in-depth exploration of plant protein modification landscapes.

Post-translational modifications (PTMs) greatly increase protein diversity and functionality. To help the plant research community interpret the ever-increasing number of reported PTMs, The Plant PTM Viewer (https://www.psb.ugent.be/PlantPTMViewer) provides an intuitive overview and tools to assess plant protein PTMs. This update includes 62 novel PTM profiling studies, adding a total of 112,000 modified peptides reporting plant PTMs, including 14 additional PTM types and three species (moss, tomato and soybean). Furthermore, an open modification re-analysis of a large-scale Arabidopsis thaliana mass spectrometry tissue atlas identified previously uncharted landscapes of lysine acylations predominant in seed and flower tissues and 3-phosphoglycerylation on glycolytic enzymes in plants. An extra 'protein list analysis' tool was developed for retrieval and assessing the enrichment of PTMs a protein list of interest. We conducted a protein list analysis on nuclear proteins, revealing a substantial number of redox modifications in the nucleus, confirming previous assumptions regarding the redox regulation of transcription. We encourage the plant research community to use PTM Viewer 2.0 for hypothesis testing and new target discovery and also to submit new data to expand the coverage of conditions, plant species, and PTM types, thereby enriching our understanding of plant biology.

Substrate and Functional Diversity of Protein Lysine Post-translational Modifications.

Lysine post-translational modifications (PTMs) are widespread and versatile protein PTMs that are involved in diverse biological processes by regulating the fundamental functions of histone and non-histone proteins. Dysregulation of lysine PTMs is implicated in many diseases, and targeting lysine PTM regulatory factors, including writers, erasers, and readers, has become an effective strategy for disease therapy. The continuing development of mass spectrometry (MS) technologies coupled with antibody-based affinity enrichment technologies greatly promotes the discovery and decoding of PTMs. The global characterization of lysine PTMs is crucial for deciphering the regulatory networks, molecular functions, and mechanisms of action of lysine PTMs. In this review, we focus on lysine PTMs, and provide a summary of the regulatory enzymes of diverse lysine PTMs and the proteomics advances in lysine PTMs by MS technologies. We also discuss the types and biological functions of lysine PTM crosstalks on histone and non-histone proteins and current druggable targets of lysine PTM regulatory factors for disease therapy.

Global View of Domain-Specific O-Linked Mannose Glycosylation in Glycoengineered Cells.

Protein O-linked mannose (O-Man) glycosylation is an evolutionary conserved posttranslational modification that fulfills important biological roles during embryonic development. Three nonredundant enzyme families, POMT1/POMT2, TMTC1-4, and TMEM260, selectively coordinate the initiation of protein O-Man glycosylation on distinct classes of transmembrane proteins, including α-dystroglycan, cadherins, and plexin receptors. However, a systematic investigation of their substrate specificities is lacking, in part due to the ubiquitous expression of O-Man glycosyltransferases in cells, which precludes analysis of pathway-specific O-Man glycosylation on a proteome-wide scale. Here, we apply a targeted workflow for membrane glycoproteomics across five human cell lines to extensively map O-Man substrates and genetically deconstruct O-Man initiation by individual and combinatorial knockout of O-Man glycosyltransferase genes. We established a human cell library for the analysis of substrate specificities of individual O-Man initiation pathways by quantitative glycoproteomics. Our results identify 180 O-Man glycoproteins, demonstrate new protein targets for the POMT1/POMT2 pathway, and show that TMTC1-4 and TMEM260 pathways widely target distinct Ig-like protein domains of plasma membrane proteins involved in cell-cell and cell-extracellular matrix interactions. The identification of O-Man on Ig-like folds adds further knowledge on the emerging concept of domain-specific O-Man glycosylation which opens for functional studies of O-Man-glycosylated adhesion molecules and receptors.

Electron Capture vs Transfer Dissociation for Site Determination of Tryptic Peptide Tyrosine Sulfation: Direct Detection of Fibrinogen Sulfation Sites and Identification of Novel Isobaric Interferences.

Tyrosine sulfation, an understudied but crucial post-translational modification, cannot be directly detected in conventional nanoflow liquid chromatography-tandem mass spectrometry (nanoLC-MS/MS) due to the extreme sulfate lability. Here, we report the detection of sulfate-retaining fragments from LC-electron capture dissociation (ECD) and nanoLC-electron transfer higher energy collision dissociation (EThcD). Sulfopeptide candidates were identified by Proteome Discoverer and MSFragger analysis of nanoLC-HCD MS/MS data and added to inclusion lists for LC-ECD or nanoLC-EThcD MS/MS. When this approach failed, targeted LC-ECD with fixed m/z isolation windows was performed. For the plasma protein fibrinogen, the known pyroglutamylated sulfopeptide QFPTDYDEGQDDRPK from the beta chain N-terminus was identified despite a complete lack of sulfate-containing fragment ions. The peptide QVGVEHHVEIEYD from the gamma-B chain C-terminus was also identified as sulfated or phosphorylated. This sulfopeptide is not annotated in Uniprot but was previously reported. MSFragger further identified a cysteine-containing peptide from the middle of the gamma chain as sulfated and deamidated. NanoLC-EThcD and LC-ECD MS/MS confirmed the two former sulfopeptides via sulfate-retaining fragment ions, whereas an unexpected fragmentation pattern was observed for the third sulfopeptide candidate. Manual interpretation of the LC-ECD spectrum revealed two additional isobaric identifications: a trisulfide-linked cysteinyl-glycine or a carbamidomethyl-dithiothreiotol covalent adduct. Synthesis of such adducts confirmed the latter identity.

Multilayered regulation and implication of flowering time in plants.

Initiation of flowering is a key switch for plants to shift from the vegetative growth to the phase of reproductive growth. This critical phase is essential not only for achieving successful reproduction, but also for facilitating environmental adaptation and maximizing yield potential. In the past decades, the environmental factors and genetic pathways that control flowering time have undergone extensive investigation in both model plant Arabidopsis and various crop species. The impact of environmental factors on plant flowering time is well documented. This paper focuses on the multilayered modulation of flowering time. Recent multi-omics approaches, and genetic screens have revealed additional components that modulate flowering time across various levels, encompassing chromatin modification, transcriptional and post-transcriptional control, as well as translational and post-translational regulation. The interplay between these various layers of regulation creates a finely-tuned system that can respond to a wide variety of inputs and allows plants to adjust flowering time in response to changing environmental conditions. In this review, we present a comprehensive overview of the recent progress made in understanding the intricate regulation of flowering time in plants, emphasizing the pivotal molecular components and their intricate interactions. Additionally, we provide an exhaustive list of key genes implicated in the intricate modulation of flowering time and offer a detailed summary of regulators of FLOWERING LOCUS T (FT) and FLOWERING LOCUS (FLC). We also discuss the implications of this knowledge for crop improvement and adaptation to changing environments.

Identification of phosphorylated small ORF-encoded peptides in Hep3B cells by LC/MS/MS.

Small ORF-encoded peptides (SEPs) are a class of low molecular weight proteins and peptides comprising <100 amino acids with important functions in various life activities. Although the sequence length is short, SEPs might also have post-translational modification (PTM). Phosphorylation is one of the most essential PTMs of proteins. In this work, we enriched phosphopeptides with IMAC and TiO2 materials and analyzed the phosphorylated SEPs in Hep3B cells. A total of 24 phosphorylated SEPs were identified, and 11 SEPs were coded by ncRNA. For the sequence analysis, we found that the general characteristics of phosphorylated SEPs are roughly the same as canonical proteins. Besides, two phosphorylation SEPs have the Stathmin family signature 2 motif, which can regulate the microtubule cytoskeleton. Some SEPs have domains or signal peptides, indicating their specific functions and subcellular locations. Kinase network analysis found a small number of kinases that may be a clue to the specific functions of some SEPs. However, only one-fifth of the predicted phosphorylation sites were identified by LC/MS/MS, indicating that many SEP PTMs are hidden in the dark, waiting to be uncovered and verified. This study helps expand our understanding of SEP and provides information for further SEP function investigation. SIGNIFICANCE: Small ORF-encoded peptides (SEPs) are important in various life activities. Although the sequence length is short (<100AA), SEPs might also have post-translational modification (PTM). Phosphorylation is one of the most essential PTMs of proteins. We enriched phosphopeptides and analyzed the phosphorylated SEPs in Hep3B cells. That is the first time to explore the PTM of SPEs systematically. Kinase network analysis found a small number of kinases that may be a clue to the specific functions of SEPs. More SEP PTMs are hidden in the dark and waiting to be uncovered and verified. This study helps expand our understanding of SEP and provides information for further SEP function investigation.

Chaperone- and PTM-mediated activation of IRF1 tames radiation-induced cell death and the inflammatory response.

The key role of structural cells in immune modulation has been revealed with the advent of single-cell multiomics, but the underlying mechanism remains poorly understood. Here, we revealed that the transcriptional activation of interferon regulatory factor 1 (IRF1) in response to ionizing radiation, cytotoxic chemicals and SARS-CoV-2 viral infection determines the fate of structural cells and regulates communication between structural and immune cells. Radiation-induced leakage of mtDNA initiates the nuclear translocation of IRF1, enabling it to regulate the transcription of inflammation- and cell death-related genes. Novel posttranslational modification (PTM) sites in the nuclear localization sequence (NLS) of IRF1 were identified. Functional analysis revealed that mutation of the acetylation site and the phosphorylation sites in the NLS blocked the transcriptional activation of IRF1 and reduced cell death in response to ionizing radiation. Mechanistically, reciprocal regulation between the single-stranded DNA sensors SSBP1 and IRF1, which restrains radiation-induced and STING/p300-mediated PTMs of IRF1, was revealed. In addition, genetic deletion or pharmacological inhibition of IRF1 tempered radiation-induced inflammatory cell death, and radiation mitigators also suppressed SARS-CoV-2 NSP-10-mediated activation of IRF1. Thus, we revealed a novel cytoplasm-oriented mechanism of IRF1 activation in structural cells that promotes inflammation and highlighted the potential effectiveness of IRF1 inhibitors against immune disorders.

Unraveling role of ubiquitination in drug resistance of gynecological cancer.

Chemotherapy is the principal treatment for advanced cancer patients. However, chemotherapeutic resistance, an important hallmark of cancer, is considered as a key impediment to effective therapy in cancer patients. Multiple signaling pathways and factors have been underscored to participate in governing drug resistance. Posttranslational modifications, including ubiquitination, glycosylation, acetylation and phosphorylation, have emerged as key players in modulating drug resistance in gynecological tumors, such as ovarian cancer, cervical cancer and endometrial cancer. In this review article, we summarize the role of ubiquitination in governing drug sensitivity in gynecological cancers. Moreover, we describe the numerous compounds that target ubiquitination in gynecological cancers to reverse chemotherapeutic resistance. In addition, we provide the future perspectives to fully elucidate the mechanisms by which ubiquitination controls drug resistance in gynecological tumors, contributing to restoring drug sensitivity. This review highlights the complex interplay between ubiquitination and drug resistance in gynecological tumors, providing novel insights into potential therapeutic targets and personalized treatment strategies to overcome the bottleneck of drug resistance.

E3 ubiquitin ligase RNF2 protects polymerase ι from destabilization.

Human DNA polymerase ι (Polι) belongs to the Y-family of specialized DNA polymerases engaged in the DNA damage tolerance pathway of translesion DNA synthesis that is crucial to the maintenance of genome integrity. The extreme infidelity of Polι and the fact that both its up- and down-regulation correlate with various cancers indicate that Polι expression and access to the replication fork should be strictly controlled. Here, we identify RNF2, an E3 ubiquitin ligase, as a new interacting partner of Polι that is responsible for Polι stabilization in vivo. Interestingly, while we report that RNF2 does not directly ubiquitinate Polι, inhibition of the E3 ubiquitin ligase activity of RNF2 affects the cellular level of Polι thereby protecting it from destabilization. Additionally, we indicate that this mechanism is more general, as DNA polymerase η, another Y-family polymerase and the closest paralogue of Polι, share similar features.

Set2 and H3K36 regulate the Drosophila male X chromosome in a context-specific manner, independent from MSL complex spreading.

Dosage compensation in Drosophila involves upregulating male X-genes two-fold. This process is carried out by the MSL (male-specific lethal) complex, which binds high-affinity sites and spreads to surrounding genes. Current models of MSL spreading focus on interactions of MSL3 (male-specific lethal 3) with histone marks; in particular, Set2-dependent H3 lysine-36 trimethylation (H3K36me3). However, Set2 might affect DC via another target, or there could be redundancy between canonical H3.2 and variant H3.3 histones. Further, it is difficult to parse male-specific effects from those that are simply X-specific. To discriminate among these possibilities, we employed genomic approaches in H3K36 (residue) and Set2 (writer) mutants. The results confirm a role for Set2 in X-gene regulation, but show that expression trends in males are often mirrored in females. Instead of global male-specific reduction of X-genes in Set2/H3K36 mutants, the effects were heterogeneous. We identified cohorts of genes whose expression was significantly altered following loss of H3K36 or Set2, but the changes were in opposite directions, suggesting that H3K36me states have reciprocal functions. In contrast to H4K16R controls, analysis of combined H3.2K36R/H3.3K36R mutants neither showed consistent reduction in X-gene expression, nor any correlation with MSL3 binding. Examination of other developmental stages/tissues revealed additional layers of context-dependence. Our studies implicate BEAF-32 and other insulator proteins in Set2/H3K36-dependent regulation. Overall, the data are inconsistent with the prevailing model wherein H3K36me3 directly recruits the MSL complex. We propose that Set2 and H3K36 support DC indirectly, via processes that are utilized by MSL but common to both sexes.

Deubiquitinating enzymes: potential regulators of the tumor microenvironment and implications for immune evasion.

Ubiquitination and deubiquitination are important forms of posttranslational modification that govern protein homeostasis. Deubiquitinating enzymes (DUBs), a protein superfamily consisting of more than 100 members, deconjugate ubiquitin chains from client proteins to regulate cellular homeostasis. However, the dysregulation of DUBs is reportedly associated with several diseases, including cancer. The tumor microenvironment (TME) is a highly complex entity comprising diverse noncancerous cells (e.g., immune cells and stromal cells) and the extracellular matrix (ECM). Since TME heterogeneity is closely related to tumorigenesis and immune evasion, targeting TME components has recently been considered an attractive therapeutic strategy for restoring antitumor immunity. Emerging studies have revealed the involvement of DUBs in immune modulation within the TME, including the regulation of immune checkpoints and immunocyte infiltration and function, which renders DUBs promising for potent cancer immunotherapy. Nevertheless, the roles of DUBs in the crosstalk between tumors and their surrounding components have not been comprehensively reviewed. In this review, we discuss the involvement of DUBs in the dynamic interplay between tumors, immune cells, and stromal cells and illustrate how dysregulated DUBs facilitate immune evasion and promote tumor progression. We also summarize potential small molecules that target DUBs to alleviate immunosuppression and suppress tumorigenesis. Finally, we discuss the prospects and challenges regarding the targeting of DUBs in cancer immunotherapeutics and several urgent problems that warrant further investigation.