
==== Front
Genes Dis
Genes Dis
Genes & Diseases
2352-4820
2352-3042
Chongqing Medical University

S2352-3042(23)00441-5
10.1016/j.gendis.2023.101158
101158
Review Article
Protein ubiquitination in ovarian cancer immunotherapy: The progress and therapeutic strategy
Guo Huiling ab1
Wei Jianwei c1
Zhang Yuyan c
Wang Li d
Wan Junhu ab
Wang Weiwei d
Gao Ling e
Li Jiajing d
Sun Ting sunting@zzu.edu.cn
ab∗∗
Ma Liwei liweimalg@126.com
ab∗
a Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
b Key Clinical Laboratory of Henan Province, Zhengzhou, Henan 450052, China
c Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
d Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
e Department of Gynecologic Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan 450052, China
∗ Corresponding author. Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe Road East, Zhengzhou, Henan 450052, China. liweimalg@126.com
∗∗ Corresponding author. Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe Road East, Zhengzhou, Henan 450052, China. sunting@zzu.edu.cn
1 These authors contributed equally to this work.

29 10 2023
11 2024
29 10 2023
11 6 1011584 6 2023
4 9 2023
10 10 2023
© 2023 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd.
2023
Chongqing Medical University
https://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Ovarian cancer is a common cancer for females, and the incidence and mortality rates are on the rise. Many treatment strategies have been developed for ovarian cancer, including chemotherapy and immunotherapy, but they are often ineffective and prone to drug resistance. Protein ubiquitination is an important class of post-translation modifications that have been found to be associated with various human diseases and cancer development. Recent studies have revealed that protein ubiquitination is involved in the progression of ovarian cancer and plays an important role in the tumor immune process. Moreover, the combination of ubiquitinase/deubiquitinase inhibitors and cancer immunotherapy approaches can effectively reduce treatment resistance and improve treatment efficacy, which provides new ideas for cancer treatment. Herein, we review the role of protein ubiquitination in relation to ovarian cancer immunotherapy and recent advances in the use of ubiquitinase/deubiquitinase inhibitors in combination with cancer immunotherapy.

Keywords

Deubiquitination
Immune-related molecules
Immunotherapy
Ovarian cancer
Ubiquitination
==== Body
pmcIntroduction

Ovarian cancer is a multifrequency female cancer, which became the second leading cause of death from gynecological cancers in China after about 2005, with the incidence and mortality rates of ovarian cancer also increasing in recent years.1 In 2020, a total of 313,959 new cases and 207,252 new deaths occurred worldwide, ranking eighth in terms of incidence and mortality of all cancers.2 Although there are new treatments available for ovarian cancer, treatment outcomes and overall survival rates for ovarian cancer have not improved because more than 70% of ovarian cancers are not diagnosed until they reach stage III or IV, and most patients experience recurrence and chemo-resistance after chemotherapy. Currently, surgery and chemotherapy are the main treatments for ovarian cancer, however, patients often experience chemo-resistant relapse within a few years after the initial treatment, so various immunotherapies are being investigated for adjuvant treatment, including immune checkpoint inhibition, adoptive T cell-receptor therapy, and intraperitoneal monocytes plus type I interferons (IFNs) as a cellular immunotherapy.3, 4, 5, 6, 7 While immunotherapy has made great progress in recent years, ovarian cancer has a limited response to immunotherapy.8,9

Ubiquitin-protein conjugation is a type of protein hydrolysis-dependent or non-dependent post-transcriptional modification. Ubiquitination is catalyzed by a three-enzyme cascade reaction consisting of E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzymes), and E3 (ubiquitin-ligase enzymes), with E3 ubiquitin-ligase enzymes playing a key role in regulating the cascade of ubiquitin transfer reactions by recognizing and catalyzing the coupling of ubiquitin to specific protein substrates.10,11 Ubiquitination is a dynamic and reversible process, the deubiquitination is catalyzed by deubiquitinating enzymes (DUBs) that perform the function of removing protein ubiquitination.11 The ubiquitination/deubiquitination process plays an important role in different aspects of the organism. On one hand, it is involved in regulating many aspects of the immune system, including the development, activation, and differentiation of lymphocytes, induction of T-cell tolerance, antigen presentation, immune evasion, and viral outgrowth. On the other hand, in addition to proteasome-mediated degradation, E3-promoted ubiquitination affects a wide range of biological processes, such as receptor down-regulation, signal transduction, protein processing or translocation, protein–protein interactions, and gene transcription.10 Ubiquitination/deubiquitination-mediated protein degradation plays an important role in cell cycle progression, signal transduction, transcriptional regulation, receptor down-regulation, and cytokinesis, among other processes.12 Several studies in recent years have shown that the process of ubiquitination is closely associated with the progression of ovarian cancer and chemotherapy resistance. F-box proteins can recruit substrates through protein–protein interactions and promote substrate ubiquitination and degradation. The F-box protein (FBP) family of E3 ubiquitin ligases such as FBXO2 and FBXO6 can contribute to the development of ovarian cancer by performing their ubiquitin ligase functions to promote the ubiquitinated degradation of their substrates. Other E3 ubiquitin ligases, like cullin 3, also promote ovarian cancer development through the ubiquitinated degradation of their substrates.13, 14, 15, 16 In addition, there are also E3 ubiquitin ligases that can inhibit the development of ovarian cancer, such as FBXO16, which also depends on the degradation of the substrate by its ubiquitin ligase activity.17 Also, deubiquitination plays a significant role in ovarian carcinogenesis, for example, deubiquitinase PSMD14 is highly expressed in ovarian cancer and promotes ovarian cancer progression by reducing the ubiquitination of substrates.18

In conclusion, ubiquitination/deubiquitination has an important effect on ovarian cancer. It was also found that ubiquitination was associated with the efficacy of chemotherapy and immunotherapy in ovarian cancer. During the process of immunotherapy, ubiquitination/deubiquitination is prone to cause a resistance to immunotherapy thus influencing the efficacy of the treatment.19,20 Moreover, the ubiquitination process has been found to influence chemoresistance in ovarian cancer, and E3 ubiquitin ligases have been shown to play a key role in chemoresistance by degrading various chemoresistance-associated substrates in ovarian cancer.21, 22, 23, 24, 25

Ubiquitination/deubiquitination process

Ubiquitin is a protein consisting of 76 amino acids.26 Ubiquitination is catalyzed by three enzymes (E1, E2, and E3); ubiquitin is first activated by E1, the activated ubiquitin binds to E2, and subsequently, E2 transfers the activated ubiquitin to the target protein recognized by E3.27, 28, 29 In most cases, the isopeptide bond is formed between the internal Lys (K) wε-amino of the substrate protein and the ubiquitin c-terminal carboxyl group.29 The key feature of ubiquitin is its seven Lys residues (K6, K11, K27, K33, K48, and K63), all of which can be ubiquitinated to produce an isopeptide-linked ubiquitin chain. The eighth chain type, Met1-linked or “linear” chain, is created when the ubiquitin is connected to the N-terminal end of the second ubiquitin.26 Among them, K48 and K63 are the most abundantly studied, but nowadays the study of ubiquitination of other species is gradually deepening.30

The deubiquitination process is catalyzed by DUBs, reversing the degradation caused by ubiquitination on the one hand and other functional changes caused by ubiquitination on the other hand.31 Depending on the different catalytic mechanisms, there are nearly one hundred known DUBs, including cysteine proteases (USPs, UCHs, MJDs, and OTOs) and metalloproteases (containing metallo-catalytic structural domains).32 DUBs are not only involved in the recycling and conversion of ubiquitinated ubiquitin, but they rearrange ubiquitin-linked proteins.33 DUBs exert deubiquitination by hydrolyzing the isopeptide bond between ubiquitin and the target protein, and all DUBs have at least one ubiquitin-binding site, such as the S1 site. S1 site selection for ubiquitination-modified proteins to deubiquitinate the ubiquitin C-terminus and scissor bond-guided active site.34 In cleavage of ubiquitin, the S1 site is occupied by distal ubiquitin while proximal ubiquitin occupies the S1 site, and besides that, some other DUBs have additional ubiquitin binding sites, such as S2 and S3 (Fig. 1).35Figure 1 The process of ubiquitination/deubiquitination.

Figure 1

Ubiquitination/deubiquitination and tumor immune

Tumor microenvironment

In the process of ovarian cancer immunotherapy, drug resistance often occurs, which affects the survival and prognosis of patients. Meanwhile, the tumor microenvironment contains a variety of immune cells, which is closely related to the immunotherapy effects. Also, many components of the tumor microenvironment are regulated by ubiquitination/deubiquitination.36

Macrophages play an important role in antitumor immunity and can be usually divided into classically activated M1 macrophages and selectively activated M2 macrophages. Tumor-associated macrophages, usually presenting as M2, act as inhibitors of the cytotoxic function of tumor-killing immune cells, thus weakening anti-tumor immunity and thereby contributing to adverse tumor outcomes as well as increasing the difficulty of treatment.37 Ubiquitination plays a prominent role in regulating macrophages, and the IGF2BP3 (insulin-like growth factor 2 mRNA-binding protein 3) protein, a known oncogenic protein promotes immunosuppressive phenotypic polarization in macrophages.38 The stability of IGF2BP3 can be down-regulated by E3 ubiquitin ligases HECTD4 and TRIM25-mediated ubiquitination to regulate tumor-associated macrophage infiltration.38,39 A recent study found that the E3 ubiquitinase UBR5 is critical for ovarian cancer progression as it promotes the recruitment and activation of tumor-associated macrophages through key chemokines and cytokines.21 Also, there was a strong relationship between the expression level of the E3 ubiquitin ligase MEX3A and the infiltration level of macrophages, neutrophils, dendritic cells, B cells, and CD8+ T cells.40 In addition to ubiquitination, deubiquitination can also regulate the progression of tumors and tumor-associated macrophage polarization. USP10 mediates the deubiquitination of NLRP3 to enhance its protein stability, which promotes the secretion of NLRP3-induced C–C motif chemokine ligand 2 and promotes the polarization of pro-tumorigenic M2-like macrophages in colorectal cancer.41

Regulatory T cells (Tregs) are necessary for the control of the immune response and the maintenance of homeostasis in the body while impeding anti-tumor immunotherapy. Several studies have also shown that ubiquitination/deubiquitination processes play an important role in the regulation of Treg. Treg exhibits instability when it loses the transcription factor Foxp3, which can promote tumor immunity, and a variety of ubiquitinases/deubiquitinases can regulate Treg by modulating Foxp3. E3 ubiquitin ligase Rnf20 inhibits Treg by promoting histone ubiquitination on the Foxp3 promoter and conserved non-coding DNA sequence regions leading to chromatin condensation and Foxp3 transcriptional deletion.42,43 In contrast, deubiquitinases alleviate ubiquitinase-induced Treg instability, and Usp22 and Usp21 maintain Foxp3 expression at the transcriptional and post-translational levels through DUB function. Hence, they regulate the metabolic program of Treg cells and promote the adaptation of Treg cells in nutrient-limited environments.43

Cancer-associated fibroblasts (CAFs) are the main cellular components that form the tumor microenvironment and are closely related to tumor growth and metastasis.44,45 Similar to macrophages and Treg, ubiquitination/deubiquitination also acts on CAFs to regulate tumor progression. Ubiquitination/deubiquitination prevents the activation of CAFs by targeting PRKN to inhibit mitochondrial autophagy, which in turn inhibits proline synthesis and induces defective autophagy in CAFs.45 In addition to this, ubiquitination/deubiquitination also plays a part in downstream of CAF. usp7 promotes the entry of CAF-derived miR522 into the exosome by stabilizing hnRNPA1 through deubiquitination, which regulates tumor progression through the usp7/hnRNPA1 axis.46 Thus, ubiquitination/deubiquitination can be involved in tumor progression by modulating CAFs or participating in CAF downstream pathways.

Tumor immune responses

A critical mechanism of cancer immune escape is defective processing and presentation of tumor antigens, including loss of major histocompatibility (MHC) expression or dysregulation of antigen processing mechanisms.47 MHC I and MHC II play a key role in the activation and regulation of adaptive immunity by presenting antigens to CD8+ or CD4+ T cells.48,49 Moreover, the ubiquitin-proteasome system has been shown to influence the process of antigen presentation by regulating the expression of MHC Ⅰ and MHC Ⅱ, thus affecting the immune process. Ubiquitin-proteasome system is widely recognized to play an important role in MHC Ⅰ regulation. A recent study estimated its contribution to MHC class I peptide production by quantitative mass spectrometry. The results revealed that ubiquitin-proteasome system is required for the production of most MHC class I peptide complexes and demonstrated in breast cancer cells that proteasome inhibitors have potential for use in cancer immunotherapy.50 First, ubiquitinase binds directly to MHC Ⅰ, ubiquitinates and degrades MHC I, and thus inhibits the expression of MHC Ⅰ. MHC Ⅰ binds to the surface protein sushi structural domain 6 and transmembrane protein 127 to form a three-molecule complex, which recruits the E3 ubiquitin ligase WWP2. Then WWP2 activates the ubiquitination and lysosomal degradation of MHC Ⅰ, leading to an effect on the antigen presentation process.51 Furthermore, ubiquitination can also indirectly regulate the expression of MHC Ⅰ. E3 ubiquitin ligase VHL can induce the activation of the JAK1/STAT1 pathway by degrading PTP1B and TC-PTP, thus promoting the expression of MCH Ⅰ in tumor cells.48 The increased expression of MHC Ⅰ contributes to increasing IFN-γ signaling and antigen presentation in tumor cells as well as promoting CD8+ T cell activation.48 In the case of MHC Ⅱ, ubiquitination can regulate the expression of MHC Ⅱ at the transcriptional level. The E3 ubiquitin ligase FBXO11 regulates MHC class II transactivator protein levels through ubiquitination-mediated degradation. MHC class II transactivator, a major regulator of MHC Ⅱ gene transcription, leads to reduced MHC II at the transcriptional level after degradation by the ubiquitinated proteasome. Thus, the E3 ubiquitin ligase FBXO11 is negatively associated with MHC Ⅱ.49 It is also known that MHC Ⅱ can be directly ubiquitinated and degraded by the E3 ubiquitin ligase MARCH1 and thus affects the antigen presentation of dendritic cells as well as humoral immunity.52 Interestingly, ubiquitination of MHC Ⅱ has also been found to influence the expression of MHC Ⅰ. The expression of MHC I on the surface can be significantly reduced by inhibiting MHC II ubiquitination, but the specific mechanism has not been fully clarified; it is speculated that MHC II and MHC I may compete for the recycling pathway, or excessive MHC II molecules disturb the microstructural domains, which makes MHC I easy to be destabilized.53 In conclusion, ubiquitination is closely associated with the expression of MHC Ⅰ and MHC Ⅱ. As MHC Ⅰ and Ⅱ mediate antigen presentation, they correlate with the efficacy of tumor immunotherapy such as checkpoint immune blockade therapy and anti-tumor antibody immunotherapy.49 Thus targeting ubiquitination and antigen presentation may help to improve the efficacy of tumor immunotherapy.

In the tumor microenvironment, antigen-presenting cells recognize tumor-derived DNA thereby driving STING signaling activation. Activation of STING signaling promotes the generation of an immune response and the activation of a T-cell-dependent anti-tumor immune response. This plays a crucial role in triggering multiple anti-tumor immune responses.54 Ubiquitination can effectively regulate this immune signaling process. The E3 ubiquitin ligase LOM7 can directly interact with STING to promote k63-linked polyubiquitination, thereby inhibiting STING signaling.54 Moreover, the ubiquitinases TRIM24 and TRIM25 can also affect STING signaling by regulating DNA signaling. TRIM25 promotes the ubiquitination and degradation of mitochondrial voltage-dependent anion-selective channel protein 2, which inhibits mitochondrial DNA released from nasopharyngeal carcinoma radiotherapy to suppress the type I interferon response produced after radiotherapy.55 TRIM24 induces the degradation of TREX1. Accumulation of cytoplasmic DNA induced by TREX1 degradation activates the cytoplasmic DNA sensing cGAS/STING pathway, leading to induction of type I interferon.56 The above ubiquitination process regulates STING signaling, which can further affect the activation of type I interferon under STING signaling, thereby influencing the inflammatory response in the tumor microenvironment.54, 55, 56 In addition, the E3 ubiquitin ligase STUB1 can directly mediate the ubiquitin-dependent proteasomal degradation of the IFNγ-R1/JAK1 complex, thereby inhibiting interferon-mediated inflammatory responses.57

Ubiquitination/deubiquitination and ovarian cancer immunotherapy

Ubiquitination/deubiquitination processes play an important role in the repair of DNA damage, regulation of the cell cycle, and immune response.58, 59, 60 Several immunotherapies have been identified for ovarian cancer treatment (Fig. 2) but with limited efficacy, and researchers have found that ubiquitination/deubiquitination can regulate ovarian cancer development in several ways and is associated with immunotherapy for ovarian cancer.8,61 Several immunotherapy-specific targets of ubiquitination/deubiquitination modifications are as follows (Table 1).Figure 2 Main mechanisms of cancer immunotherapy that can be modulated by ubiquitination/deubiquitination. CAR, chimeric antigen receptor; Kyn, kynurenine; IDO1, indoleamine 2,3-dioxygenase 1; PD-1, programmed cell death-1; PD-L1, programmed cell death-ligand 1; TME, tumor microenvironment; Trp, tryptophan.

Figure 2

Table 1 Several specific immune-related targets of ubiquitination/deubiquitination modification.

Table 1Molecules	Enzymes	Ubiquitin chain	Modification sites	Cancer types	Functions	Reference	
PD-L1	β-TRCP	__	__	Ovarian cancer	It promotes intracellular PD-L1 ubiquitinated proteasome degradation, enabling PD-L1 treatment-insensitive tumor cells to become sensitive and promoting immune checkpoint blockade treatment.	73	
USP7	__	__	Gastric cancer	USP7 deubiquitinates PD-L1 as a deubiquitinating enzyme, which stabilizes PD-L1 and inhibits anti-tumor immunity.	70	
FBXO22	__	__	Lung adenocarcinoma	FBXO22 ubiquitinates and degrades PD-L1 through proteasome-mediated degradation, and sensitizes cancer cells to DNA damage.	71	
IDO1	USP14	K48	__	Colorectal cancer	It deubiquitinates and stabilizes IDO1 to prevent the degradation of IDO1 by TRIM21, thus promoting tryptophan metabolism and immunosuppression.	81	
TRIM21	K48	__	Colorectal cancer	It ubiquitinated and degraded IDO1, inhibiting IDO1-mediated tryptophan metabolism and immunosuppression.	81	
p53	RBX1	__	__	Ovarian cancer	It increases the proliferation and decreases the apoptosis of tumor cells by enhancing ubiquitination and proteasome degradation of p53.	95	
Parkin	__	__	Ovarian cancer	It mediates p53 ubiquitination and proteasome degradation that inhibits the proliferation of ovarian cancer cells.	96	
SMYD3，UBE2R2	__	__	Epithelial ovarian cancer	SMYD3 promotes the transfer of p53 from the nucleus to the cytoplasm and interacts with UBE2R2 to promote the ubiquitinated degradation of p53 which enhances the migration ability of epithelial ovarian cancer cells.	97	
mtp53	TRIM27	K11, K27, K29, K63	__	Ovarian cancer	It promotes the ubiquitination and degradation of mtp53, thereby inhibiting the proliferation and invasion of ovarian cancer cells.	99	
DTX3/RNF154	K11, K27, K29, K33, K48, K63	__	Ovarian cancer	It inhibits the binding of MDM2 to p53 by ubiquitinating mtp53, resulting in the stabilization of p53 and promoting the growth and proliferation of ovarian cancer cells.	98	
mtp53-R175	USP15	__	__	Ovarian cancer	Loss of USP causes the ubiquitination of p53-R175 and the degradation by lysosomes, which reduces the viability of cancer cells.	100	
CAR	K3/K5	__	__	__	It mediates ubiquitinated degradation of MHC I/II on CAR-T to evade the host immune response and maintain the survival of CAR-T cells	111	
Frizzled (FZD)	RNF43	__	__	Gastric cancer	RNF43 mediates ubiquitination and lysosomal degradation of FZD, thereby inhibiting Wnt/β-catenin signaling pathway activation.	125	
c-MYC protein	TRIM37, HUWEI	__	__	Ovarian cancer	TRIM37 promotes the expression of c-MYC by targeting HUWE1.	139	
β-catenin	UBE2S, APC/C	K11	K19	High-grade plasma ovarian cancer	UBE2S interacts with the APC/C complex to ubiquitinate the K19 residue of β-catenin and improve its stability, thereby preventing its degradation and activating the Wnt/β-catenin signaling pathway.	134,135	
UCHL5	__	__	Endometrial cancer	UCHL5 inhibits ubiquitinated proteasome degradation of β-catenin and activates the Wnt/β-catenin signaling pathway.	136	

PD-L1

Programmed death-ligand 1 (PD-L1, CD274) is a B7 homologous family immune co-signaling molecule that interacts with programmed death-1 (PD-1), a receptor on T cells and natural killer cells, to inactivate both T and natural killer cells, thus attenuate anti-tumor immune responses and allow tumors to evade immune surveillance (Fig. 3A).62, 63, 64 Drugs that block PD-1 or PD-L1 promote endogenous anti-tumor immunity and have been considered the common standard of care for cancer treatment due to their broad spectrum of activity.62 In addition, PD-L1 protects tumor cells from the cytotoxic effects of type I and type II interferons and cytotoxic T lymphocyte-mediated cell lysis, which is a process that does not require PD-1 signaling in T cells.65 Therefore, PD-L1 is an effective target for regulating tumor immunity. Anti-PD-L1 antibodies are thought to play an important role in the adjuvant treatment of ovarian cancer,66 and PD-L1 may be a prognostic indicator for ovarian cancer.67 Recently, it has been shown that the regulation of PD-L1 includes degradation through ubiquitination,20 suggesting that ubiquitination is involved in PD-L1 immunotherapy. Immune checkpoint blockade (ICB) is well known and studied for its ability to counteract PD-L1 expressed on the cell surface, but recent evidence on cell-intrinsic PD-L1 signaling in immunopathogenic tumors suggests an additional role for cell-intrinsic PD-L1 beyond its typical surface role. These roles are important in treatment resistance, where in particular they are in the resistance of oncology treatments to different classes of therapies, including cytotoxic drugs, targeted small molecules, radiation, and immunotherapy.68Figure 3 PD-L1 with ubiquitination/deubiquitination. (A) PD-L1/PD-1 can block the killing of tumor cells by T cells and natural killer (NK) cells. (B) The ubiquitinase β-TRCP and FBXO22 induce PD-L1 ubiquitination and proteasomal degradation, while the PD-L1-depleting drugs cefepime and chlorambucil promote PD-L1 ubiquitination and proteasomal degradation in ovarian cancer cell lines. The deubiquitinase USP7 removes the ubiquitination of PD-L1. (C) Ubiquitinated degradation of PD-L1 inhibits the repair of DNA damage, makes cells more sensitive to DNA damage, and activates STING signaling to overcome immune checkpoint blockade (ICB) resistance. PD-1, programmed death-1; PD-L1, programmed death-ligand 1; UB, ubiquitin.

Figure 3

Murine double minute 2 (MDM2), an E3 ubiquitin ligase, is highly expressed in ovarian clear carcinoma cells, and MDM2 was found to inhibit T cell-mediated tumor killing induced by ICB; AMG232 is a selective MDM2 inhibitor. The combination of AMG232 and anti-PD-L1 therapy can increase the ability of T cells to kill tumors and overcome drug resistance, suggesting that the potential of E3 ubiquitin ligase as a target to participate in PD-L1 ICB therapy, but the exact mechanism is not yet clear and further in vivo experiments are needed for its verification.69 In the course of studies on other types of tumors, ubiquitinating and deubiquitinating enzymes have been found to regulate PD-L1 expression, for example, the deubiquitinating enzyme USP7 removes PD-L1 ubiquitination in gastric cancer cells70 and stabilizes PD-L1; the E3 ligase FBXO22 ubiquitinates and proteasomal degrades PD-L1.71 Therefore, the role of ubiquitination and deubiquitination in the regulation of PD-L1 in ovarian cancer still holds a lot of room for exploration. In addition to the classical cancer therapeutic function of surface PD-L1, cell-intrinsic PD-L1 in tumor cells has also been shown to be involved in tumor immunity and regulated by ubiquitination. FDA-approved PD-L1-depleting drugs such as cefepime72 and chlorambucil73 promote ubiquitination and proteasomal degradation of PD-L1 in ovarian cancer cell lines to regulate PD-L1 expression, and chlorambucil relatively selectively degrades PD-L1 from tumor cells rather than stromal or local immune PD-L1 degradation by ubiquitination in cells.73 Chlorambucil has been found to promote intra-cellular PD-L1 ubiquitination via the E3 ligase β-TRCP and GSK3β/β-TRCP-mediated degradation of the PD-L1 proteasome.73 However, the specific mechanism by which cefepime promotes ubiquitinated degradation of PD-L1 has not been shown,72 and in vivo studies are needed for further validation. Chloramphenicol and cefepime reduce DNA damage repair by inhibiting cell-intrinsic PD-L1, and the increased DNA damage activates the immunogenic STING pathway.72,73 STING pathway activation was found to induce cell surface PD-L1 expression, which provides favorable conditions for ICB treatment.74 In addition, chloramphenicol increased the expression of natural killer cells in the tumor immune microenvironment and improved anti-tumor immunity, which is beneficial for ICB therapy, but this area still requires further research.73

In conclusion, ubiquitination/deubiquitination can regulate the expression of intrinsic and classical PD-L1, thus affecting tumor immunotherapy (including ICB), but its efficacy in vivo and specific mechanism have not been proved yet (Fig. 3B). Therefore, the combination of ubiquitination/deubiquitination and PD-L1 for tumor immunotherapy has great research potential and significance.

IDO1

Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-containing enzyme that catalyzes the breakdown of tryptophan (trp), which is essential for immune function, to kynurenine (kyn), thereby inhibiting CD8+ T cell activity and up-regulating immunosuppressive Treg, resulting in the inability of the immune system to respond appropriately to cancer cells, and thus IDO1 is considered an important target for cancer immunotherapy (Fig. 4A).75 Similar to PD-1/PD-L1, cancer cells have been found to evade the host immune response by inhibiting immune surveillance through the IDO pathway.76,77 IDO1 has now been shown to be highly expressed in ovarian cancer, which is strongly correlated with the infiltration of immune cell populations, especially dendritic cells and T cells, being an important immune-related gene in ovarian cancer.78Figure 4 IDO1 with ubiquitination/deubiquitination. (A) Basic function of IDO1. IDO1 promotes the conversion of tryptophan (Trp) to kynurenine (Kyn), which up-regulates immunosuppressive Treg and inhibits the activity of CD8+ T cells thereby suppressing tumor cell killing by the immune system. NTRC (NTRC3883-0) and EPA (epacadostat) can inhibit IDO1-promoted conversion of Trp to Kyn. (B) The process of ubiquitination and deubiquitination of IDO1. The ubiquitinase TRIM21 can mediate the ubiquitination of IDO1 as well as proteasomal degradation. The deubiquitinase USP14 deubiquitinates IDO1 to reduce its degradation, and the IU1, an inhibitor of USP, inhibits the deubiquitination of IDO1. Decreased levels of IDO1 can reverse the immune tolerance of tumors. IDO1, indoleamine 2,3-dioxygenase 1.

Figure 4

Various IDO1 inhibitors have been found to improve IDO1-mediated immunosuppression of tumor cells by inhibiting the IDO1 pathway, including NTRC 3883-0 and epacadostat (INCB024360, EPA). Among them, although NTRC 3883-0 can inhibit IDO1, the acceptable dose for cancer patients makes clinical use less meaningful.79 EPA is an oral reversible competitive IDO1 inhibitor, but studies found that its treatment as an IDO1 inhibitor was not successful, which seemed to eliminate enthusiasm for IDO1 research, however, subsequent studies identified the problem. The inhibition of IDO1 leads to metabolic adaptation that promotes the NAD+ biosynthetic pathway, which inhibits T cell proliferation and expression, and A2a and/or A2b purinergic receptor antagonists were found to block NAD+ inhibition of T cells, thereby ameliorating the metabolic adaptation induced by IDO1 inhibition and promoting tumor immunity.80 In general, although IDO1 inhibition can be improved by the combination of drugs, there are still many limitations in the use of IDO1 inhibitors, so it is necessary to explore new methods of IDO1 inhibition to lift tumor immunosuppression.

A new study has shown that ubiquitination/de-ubiquitination has a regulatory effect on IDO1 and does not cause AHR activation which leads to treatment ineffectiveness. The ubiquitinating enzyme TRIM21 mediates IDO1 ubiquitination and proteasomal degradation, while the deubiquitinating enzyme USP14 deubiquitinates IDO1 to stabilize it and prevent it from being degraded by TRIM. The ubiquitination/deubiquitination process of IDO1 is mediated by the K48-linked ubiquitin chain, and experiments have shown that the USP inhibitor IU1 can effectively inhibit IDO1 deubiquitination and reduce IDO1 levels, thereby reversing tumor immune tolerance and making tumor cells more sensitive to anti-PD-1.81 In conclusion, ubiquitination/deubiquitination as one of the mechanisms regulating post-translation modifications of IDO1 holds promise as a therapeutic target for cancer and has potential for combination therapy with ICB, but further in vivo experiments are needed for its validation (Fig. 4B).

p53

p53 protein is encoded by TP53 gene located on chromosome 17p13.1 and is essential for the normal course of the cell cycle. One of the main functions of p53 protein is to activate the transcription of genes that initiate apoptosis in response to DNA damage, and this function is involved in its antitumor activity.82,83 Overexpression of p53 protein has been found in 50%–60% of ovarian cancers, which is associated with mutations in p53. 96% of high-grade serous ovarian cancer cases have p53 mutations, while clear cell ovarian cancer and endometrioid ovarian cancer usually do not carry TP53 mutations.84, 85, 86 p53 plays an important role in the development of ovarian cancer and its immunotherapy. Serum concentrations of anti-p53 autoantibody complexes have been found to be significantly increased in ovarian cancer patients and play an important role in the development of plasma ovarian cancer, as well as affecting survival rates.87,88 Meanwhile, p53 was found to be associated with tumor immune cell infiltration, including induction of p53-specific memory T cell responses with the production of cytokines89 and promotion of infiltration by tumor-associated macrophages,90 thereby regulating the tumor microenvironment, which makes p53 a possible target for ovarian cancer immunotherapy (Fig. 5A). The use of p53 to construct tumor vaccines has been extensively studied, and several studies to date have shown that p53 vaccines (including p53 synthetic long peptide vaccine, p53MVA vaccine) can induce specific T cell responses by APC treatment, resulting in increased frequency of CD4+ T cells, CD8+ T cells, and decreased Treg levels. In which the p53MAV vaccine drives an increase in the number of PD-1+ CD8+ T cells in cancer patients, which increases the likelihood of enhanced immunotherapy efficacy in combination with PD-1/PD-L1.91, 92, 93, 94Figure 5 p53/mtp53 with ubiquitination/deubiquitination. (A) p53 and tumor microenvironment. p53 can regulate the tumor microenvironment by inducing p53-specific memory T-cell responses and infiltration of tumor-associated macrophages. (B) A variety of ubiquitinases can catalyze the ubiquitination and proteasomal degradation of p53, including RBX1, Parkin, SYMD3, and UBE2R2. TRIM71 promotes the ubiquitination and proteasomal degradation of mtp53, while the ubiquitinase DTX3 antagonizes the MDM2-mediated ubiquitinated degradation of mtp53 by ubiquitinating mtp53. The deubiquitinase USP15 then mediates the deubiquitination of mtp53. The ubiquitination/de-ubiquitination process of p53/mtp53 controls tumor cell apoptosis by regulating the expression of p53/mtp53.

Figure 5

Ubiquitination and deubiquitination have been found to regulate the expression of p53, both wild-type p53 and mutant p53, with selective specificity for ubiquitination of mtp53. Firstly, several studies on ubiquitination/ubiquitination of wild-type p53 revealed that ubiquitinase/deubiquitinase can regulate the expression of wild-type p53, thus regulating the proliferation and metastasis of tumor cells. E3 ubiquitinase RBX1 can interact with p53 and mediate the ubiquitinated degradation of p53, which inhibits the oncogenic function of p53, thereby increasing tumor cell proliferation and reducing their apoptosis.95 Similarly, the E3 enzyme Parkin can increase the ubiquitinated degradation of p53 and inhibit the growth of ovarian cancer cells; moreover, this process can be promoted by metformin, which provides a new mechanism for the treatment of ovarian cancer with metformin.96 It was found that SYMD3 interacts with the E2 enzyme UBE2R2 to promote the ubiquitinated degradation of p53, thereby promoting the metastasis of ovarian cancer and enhancing the migration of epithelial ovarian cancer cells, hypothesizing that SYMD3 may have a similar function to that of E3 enzymes.97 Secondly, the ubiquitination and deubiquitination of mutant p53 were also investigated. There are many p53 variants in ovarian cancer, so the regulation of mutant p53 is also very important. E3 enzyme DTX3 (also known as RNF154) mediates ubiquitination of mtp53 and maintains stability of mtp53 by preventing MDM2-mediated ubiquitinated degradation of mtp53, thus exerting the pro-oncogenic effect of mtp53 to promote the growth and proliferation of ovarian cancer cells.98 Unlike DTX3, which stabilizes mtp53, TRIM71 promotes ubiquitination of mtp53 and proteasomal degradation to destabilize mtp53, thereby inhibiting the growth and invasion of ovarian cancer cells.99 It was found that ubiquitinase and deubiquitinase selectively bind to different mutation types of p53 and mediate ubiquitination and deubiquitinase, for example, the deubiquitinase USP15 specifically modifies the P53-R175H mutation type,100 but the ubiquitinase MDM2 can regulate the p53-R248Q mutation type.24 This strategy of selectively regulating oncogenic mtp53 protein provides ideas for personalized treatment of cancer patients, which can correspond to the type of p53 mutation.

In conclusion, p53, as a proven immunotherapeutic target in ovarian cancer, plays an important role in the development, progression, and immunotherapy of ovarian cancer and can be modulated by ubiquitination and deubiquitination modifications (Fig. 5B). However, few studies have combined p53 ubiquitination and deubiquitination with immunotherapy, and further experiments are needed to explore the possibility of combination use.

CAR-T

Chimeric antigen receptor (CAR) T-cell therapy is a rapidly evolving therapeutic approach in adoptive cell transfer therapy, where artificial T cell receptors are generated by genetically engineering modified T cells. CAR is a recombinant receptor consisting of three components, an extracellular antigen recognition domain, an intracellular signaling domain involved in T-cell activation and killing, and a CD3ζ T-cell activation domain, which targets and destroys tumor cells. While CAR-T cell therapies have been highly successful in the treatment of hematological diseases, they are still under-researched for solid tumors, such as ovarian cancer.101,102 Firstly, CAR-T can directly target and kill tumor cells. It was found that mesothelin is highly expressed in ovarian cancer, and MSLN CAR-T cells can target and kill tumor cells with strong anti-tumor activity, and clinical reports showed that it has safety and efficacy.103,104 Due to the heterogeneity of ovarian cancer, single-target CAR-T cell therapy often leads to recurrence, so the study explored the efficacy of dual-target CAR-T cells. Several studies have shown that dual-target CAR-T cell therapy has stronger anti-tumor properties, such as MLSN constructing dual-target CAR-T cells with CD40,105 FOLR1 (folate receptor 1)106 and TAG-72 and CD47 dual-target CAR-T cells,107 which were found to have stronger anti-tumor performance than single-target CAR-T cells against cells with stronger killing ability (Fig. 6A). Secondly, CAR-T can regulate the tumor microenvironment and improve the ability to kill tumor cells. For example, for the regulation of tumor-associated macrophages and resident memory T cells, targeting the macrophage marker F4/80, CAR-T cells can target tumor-associated macrophages to suppress them and provide enhancement of tumor immunity,108 and CAR-T cells targeting CXCR6 can regulate resident memory T cells and thus modulate tumor immunity.109 Also, the combination of two CAR-T cells targeting tumor cells and targeting tumor microenvironment has been shown to improve the effectiveness of treatment and perform better anti-tumor function. Pretreatment with folate receptor beta-specific CAR-T cells prior to anti-mesothelin CAR-T cell therapy can modulate the tumor immune microenvironment and improve the effectiveness of anti-mesothelin CAR-T cells, which is conducive to better therapeutic effects.110Figure 6 CAR-T cell immunotherapy with ubiquitination/deubiquitination. (A) Dual-targeted CAR-T cells have a strong anti-tumor activity to damage tumor cells. (B) The interaction between tumor antigen and CAR can promote the ubiquitination of CAR and its degradation by lysosomes. The ubiquitinase K3 and K5 proteins can promote the ubiquitination and lysosomal degradation of MCH I/II, thus blocking the recognition of CAR-T cells by the CD8+ T cells in the body, preventing the immune rejection reaction, and facilitating the survival of CAR-T cells for better therapeutic effects. CAR, chimeric antigen receptor.

Figure 6

However, there are still many problems with CAR-T cell therapy, which has been found to be regulated by ubiquitination/deubiquitination, and ubiquitination/deubiquitination can improve the survival of CAR-T cells as well as the therapeutic effect. On the one hand, ubiquitination/deubiquitination can regulate the survival of CAR-T cells. Although off-the-shelf CAR-T cells can be produced in large quantities and used in multiple patients, the immune rejection caused by human leukocyte antigen (HLA) differences that affect CAR-T cell survival cannot be ignored. The E3 ubiquitin ligases K3 and K5 derived from human herpes virus-8 were found to ameliorate this immune rejection response due to the ubiquitous degradation of MHC I and II on CAR-T cells by K3 and K5, thereby evading the host immune response and maintaining the survival of off-the-shelf cells.111 Similarly, the E3 ubiquitin ligase Cbl-b can also regulate the survival of CAR-T cells, and CAR-T cells are resistant to endogenous depletion in the absence of Cbl-b, but the exact mechanism is not yet clear.112 On the other hand, ubiquitination regulation can also modulate CAR-T cell efficacy by affecting CAR signaling expression. Tumor antigen-stimulated rapid ubiquitination of CAR can lead to CAR lysosomal degradation, and when its ubiquitination is blocked, it can effectively enhance CAR signaling and improve the persistence of CAR-T cells with better tumor-killing ability.113 In addition to this, the E3 ubiquitin ligase UBR5 promotes the formation of immunosuppressive tumor microenvironment in ovarian cancer by regulating cytokines. The immunosuppressive microenvironment is improved when UBR5 is inhibited, resulting in improved therapeutic efficacy of CAR-T.21

Overall, the process of ubiquitination can modulate the efficacy of CAR-T cell therapy by regulating CAR signaling on CAR-T cells as well as the survival of CART cells, and thus ubiquitination is a potential target for tumor immunotherapy in combination with CAR-T (Fig. 6B). However, current mouse model studies do not fully mimic the in vivo conditions of cancer patients, and further clinical trials are needed for further exploration.

TCR-T

TCR-T is similar to CAR-T and is an adoptive cell transfer therapy, but unlike the limited role of CAR-T in solid tumors, TCR-T has a better therapeutic effect in solid tumors.114,115 Engineered T-cell receptors (TCRs) are used to activate TCR-T cells to exert a killing effect by modifying TCRs to recognize tumor-expressed antigens. The reason why TCR-T has better efficacy in solid tumors is that TCR-T not only recognizes antigens on the surface of the tumor but also recognizes intracellular proteins presented by MHC, which greatly increases the pool of targeted antigens for TCR-T therapy.116 However, this also suggests that TCR-T cell therapy is MHC-restricted and relies on the presentation of MHC molecules to recognize targets and activate T-cell function, while loss of HLA-1 somatic cells in immunologically “cold” tumors also negatively affects the efficacy of TCR-T.117 Thus, CAR-T cells recognize surface antigens mainly outside the tumor, whereas TCR-T can penetrate the tumor and have a better therapeutic environment.114,116 In addition, TCR-T signal lasts longer than CAR-T, which is related to the fact that TCR itself exists in the body's immune system without causing immune rejection and immune memory of TCR-T.114,117

The benefits of TCR-T in immunotherapy for solid tumors are also seen in ovarian cancer. TCR-T has great therapeutic potential for ovarian cancers, especially highly aggressive cancers such as highly plasmacytoid cancers (high-grade serous ovarian cancer) and ovarian sarcomas (ovarian carcinosarcoma), which are often considered “cold” tumors.117 Targeting TCRs against the cancer assessment antigens NY-ESO1, MAGE-A4, and PRAME has been studied in clinical trials in patients with ovarian cancer.117 Recent studies have found that PRAME and CTCFL are highly expressed as tumor-specific tumor-associated antigens in ovarian cancer, and a series of TCR-T cells constructed such as PRAME TCR (DSK3PRAME/QLL/A2, 16.3C1RAME/LYV/A24 and 8.10C4PRAME/SPS/B7) and CTCFL TCR (39.2 E12CTCFL/KLH/A2) showed potent and specific anti-tumor responses in vitro and in vivo, showing promise as effective agents for ovarian cancer treatment.118 The absence of somatic HLA class I is a widespread mechanism of immune evasion, which affects the therapeutic efficacy of TCR-T since TCR-T recognition is dependent on the presentation of MCH molecules.119 A previous study showed that ubiquitination can regulate HLA-1 expression, but not in a direct way. P53 can up-regulate endoplasmic reticulum aminopeptidase 1 expression by binding to a homologous response element in the ERAP1 gene, resulting in increased HLA1 expression. MDM2 can regulate this process by degrading p53 through ubiquitination, and thus antagonizing this ubiquitination process can effectively increase the expression of HLA1, which may help to ensure the efficacy of TCR-T.120,121 Further research is needed to explore more effective treatment options.

Wnt/β-catenin signaling pathway

The Wnt/β-catenin signaling pathway is a highly evolutionarily conserved pathway that regulates key functions such as cell proliferation, differentiation, migration, genetic stability, apoptosis, and stem cell renewal.122 Wnt pathway has been shown to play a role in ovarian cancer development.123 Previous studies have found that the Wnt pathway is closely related to cancer cell growth and metastasis, and recently there is increasing evidence that the signaling of the Wnt pathway is related to the immunological regulation of the tumor microenvironment in ovarian cancer. One target in the Wnt/β-catenin signaling pathway is the ligand, Wnt itself, which controls the activity of the pathway, and the Wnt ligand is secreted from the cell after modification by PORCN enzymes to promote signal transduction.124 Wnt ligand binds to its two receptors Frizzled (FZD) and low-density-lipoprotein-associated receptors 5 and 6 and initiates intracellular signaling through β-catenin.125 AXIN and G3K3β form a “destruction complex” and activate the degradation of β-catenin. After Wnt binds to FZD, Dvl (Dishevelled) is activated and recruits the “destruction complex” to the cell membrane, thus inhibiting the degradation of β-catenin, inducing β-catenin activation and translocation to the nucleus, then activating the Wnt signaling pathway.126 Dickkopf-1 is a Wnt target gene that encodes a dickkopf-1 protein that competes with Wnt ligands for LRP5/6 binding and negatively regulates the Wnt pathway.127 The specific features of ovarian malignancies are poor tumor antigenicity and relative immune cell deficiency.128 Recent studies have found that β-catenin levels are associated with T cell rejection and tumor growth, that immune cell infiltration in the ovarian cancer tumor microenvironment can be regulated by modulating signal transduction in the Wnt pathway, that the PORCN inhibitor CGX-1321 increases infiltration of CD8+ T cells into the tumor microenvironment, and that DDK1 overexpresses myeloid-derived suppressor cells to promote immune evasion.129,130 Initially, the combination of CGX-1321 and DKN-01 (a DDK1 inhibitor) was not found to increase CD8+ T cell levels more significantly, but a subsequent study showed that DKN-01 increased HLA/MHC I expression in ovarian cancer tissues, which could increase their antigenicity and reduce immune escape. When treated with DKN-01 followed by CGX-1321, known as Sequential Wnt modulation, a variety of leukocytes are recruited into the tumor microenvironment by modulating Wnt signaling, including B cells and macrophages in addition to CD8+ T cells.131,132 In summary, the Wnt pathway can regulate the infiltration of multiple immune cells in the tumor microenvironment of ovarian cancer and has the potential to become a target axis for immunotherapy in oncology (Fig. 7A).Figure 7 Wnt/β-catenin signaling pathway with ubiquitination/deubiquitination. (A) The Wnt signaling pathway regulates the infiltration of B cells, T cells, and macrophages in the tumor microenvironment, thereby affecting the anti-tumor immune response. (B) Wnt binds to the ligand FZD (Frizzled), which activates Dvl (Dishevelled) and recruits the “destruction complex” composed of AXIN and G3K3 β, thereby reducing the degradation of β-catenin and inducing β-catenin transfer to the nucleus. The ubiquitinase RNF43 catalyzes the ubiquitination and lysosomal degradation of FZD, thereby inhibiting the Wnt signaling pathway. The ubiquitinase UBE2S binds to APC/C to promote ubiquitination of β-catenin, enhance its stability, facilitate its translocation from the cytoplasm to the nucleus, and activate the Wnt signaling pathway. The deubiquitinase UCHL5 deubiquitinates β-catenin and reduces its degradation.

Figure 7

It was found that the Wnt signaling pathway in ovarian cancer can be regulated by ubiquitination/deubiquitination, including ubiquitinated beta proteins, FZD, and c-MYC proteins downstream of the Wnt pathway. The E3 ubiquitin ligase RNF43 can induce FZD ubiquitination and lysosomal degradation to negatively regulate the Wnt pathway, but RNF43 mutations are found in ovarian cancer, and its mutation frequency is second only to KRAS in mucinous ovarian cancer. Some of the mutations do not change their ability to negatively regulate the Wnt pathway, but the R117fs shift code mutation loses its negative regulation of the Wnt pathway to enhance the Wnt signaling pathway, and this induction of Wnt signaling pathway enhancement was inhibited by the Wnt inhibitor LGK974, suggesting that the Wnt pathway activity can be regulated by altering the E3 ubiquitin ligase.125,133 However, unlike the ubiquitinated degradation of FZD, β-catenin can be ubiquitinated to improve its stability and prevent its degradation.134 The E2 enzyme UBE2S is up-regulated in high-grade serous ovarian cancer, and the E2 enzyme UBE2S forms a complex with the E3 enzyme APC/C to promote the formation of a K11-linked ubiquitin chain from the k19 residue of the β-catenin, facilitating its accumulation in the cytoplasm and translocation to the nucleus, thereby activating the Wnt signaling pathway.134,135 In addition, the E3 ubiquitin ligases MARCH7 and MARCH1 and the DUB UCHL5 can also regulate β-catenin expression and thus the Wnt pathway, but the exact mechanism remains to be investigated.136, 137, 138 A recent study demonstrated that the E3 ubiquitin ligase TRIM37 binds to HUWEI and inhibits c-MYC protein expression, thereby affecting the Wnt pathway, but the exact mechanism needs to be investigated in depth.139

In conclusion, the Wnt pathway serves as a novel and effective pathway for regulating immune cell infiltration in the tumor microenvironment and can be regulated by ubiquitination and deubiquitination. Thus, the potential exists for ubiquitination and deubiquitination as a means of tumor immunotherapy (Fig. 7B). However, studies are not yet well established and further research is needed.

Combined application of ubiquitinase/deubiquitinase inhibitors and other immunotherapeutic strategies

Protein post-translational modifications were found to play an important role in cancer development and have potential as cancer therapeutic targets.140 As key enzymes involved in the ubiquitination/deubiquitination process, E3 ubiquitin ligases and DUBs can both play a role in cancer immunotherapy, despite their opposing functions in regulating protein stability and potentially leading to different physiological responses. E3 ubiquitin ligases promote the process of ubiquitination, and the inhibitors of these enzymes can play a role in tumor immunotherapy by inhibiting the process.141,142 DUB inhibitors also play a role in combination with tumor immunotherapy by inhibiting the process of deubiquitination.142,143 Many inhibitors of E3 ubiquitin ligases and DUBs have been studied and found to affect the immune response against cancer cells, which in combination with other immunotherapeutic approaches can effectively reduce therapeutic resistance and improve therapeutic efficacy (Table 2).70,144Table 2 Combined application of ubiquitinase/deubiquitinase inhibitors and immune checkpoint inhibitors/cancer vaccines/anti-tumor antibodies.

Table 2Combined application	Ubiquitin/deubiquitinating enzyme	Inhibitors	Combined immune checkpoint inhibitors	Phases	Cancer types	Effects	Reference	
Immune checkpoint inhibitors	cIAP1/2, XIAP	ASTX660	PD-1 antibody
XRT	Pre-clinical	Head and neck squamous cell carcinoma	It promotes the sensitivity of tumor cells to TNF-α and enhances the killing effect of T cells on tumor cells.	155	
IAP	Birinapant	PD-1 antibody	Pre-clinical	Colon cancer	It makes tumor cells more sensitive to TNF-mediated killing, and the combination with PD-L1 inhibitors further enhances the killing ability of tumor cells.	156	
cIAP1/2	LCL161	PD-1 antibody/cytotoxic T-lymphocyte antigen 4 antibody	Pre-clinical	Glioblastoma	It sensitizes tumors to TNF-α-induced killing, enhances the activity of cytotoxic T cells against tumors, and enhances the effect of immune checkpoint inhibitors in combination with immune checkpoint inhibition therapy.	158	
cIAP1/2	LCL161	PD-1 antibody	Pre-clinical	Multiple myeloma	It can modulate the tumor microenvironment and induce powerful immune activation, thus stimulating anti-tumor phagocytic activity and durable anti-tumor immunity.	157	
MDM2	APG-115	PD-1 antibody	Pre-clinical	Liver cancer, colon adenocarcinoma	It inhibits ubiquitinated degradation of p53 caused by MDM2, regulates the infiltration of immune cells in the tumor microenvironment, and enhances anti-PD-1 efficacy.	148	
MDM2	AMG-232	Pembrolizumab	Pre-clinical	Ovarian clear cell carcinoma	It targets MDM2 and enhances T cell-mediated tumor killing.	69	
MDM2	HDM201	Anti-PD-1 antibody, anti-PD-L1 antibody	Pre-clinical	Colon cancer	It inhibits the interaction between MDM2 and P53, increases dendritic cells, up-regulates CD8+/Treg ratio, and promotes durable tumor-specific immune responses to improve anti-PD-1/PD-L1 immune responses.	160	
USP7	P5091	PD-1 antibody	Pre-clinical	Lung cancer	It inhibits the activity of Treg and preserves the function of T cells as effector cells to promote anti-tumor immunity.	161	
Cancer vaccines	USP7	P5091	Adenovirus vaccines	Pre-clinical	Lung cancer	It inhibits the activity of Treg and preserves the effector cell function of T cells to promote anti-tumor immunity.	161	
IAP	M1	B16 vaccines (GVAX)	Pre-clinical	Melanoma	It enhances the response of CD4+ CD8+ T cells, and other anti-tumor cells, which can be used in combination with tumor vaccines to enhance the therapeutic effect.	166	
MDM2	Nutlin-3	MDM232-46 peptide vaccine	Pre-clinical	Head and neck squamous cell carcinoma	It blocks the interaction of MDM2 with p53, up-regulates the expression of tumor HLA to enhance the anti-tumor response of MDM2-specific T cells, and promotes vaccine-induced T cell killing of tumors.	120	
IAP2, XIAP	Smac mimetic	BCG	Pre-clinical	Bladder cancer	It promotes the killing of tumor cells by acting through TNF-α secreted by BCG-stimulated neutrophils.	167	
Anti-tumor antibody	USP1	Pimozide	Rituximab	Pre-clinical	Large B-cell lymphoma	It inhibits the USP1-mediated deubiquitination of MAX/MYC protein, which helps to reduce the resistance to rituximab treatment and inhibits the proliferation of rituximab-resistant cells.	179	
CAR-T	IAP	Birinapant	CAR-T	Pre-clinical	Breast cancer	It sensitizes tumor cells to CAR-T cell-derived TNF, significantly enhancing the antitumor activity of CAR-T lymphocyte therapy in vitro and in vivo.	169	

Combined application of ubiquitinase/deubiquitinase inhibitors and ICBs

Today's cancer immunotherapy has become an effective cancer treatment, with ICBs approved for the treatment of multiple different cancers, the more common being ICB against cytotoxic T-lymphocyte antigen 4 or PD-1-PD-L1 axis.145 Although ICBs have been used to treat a variety of cancers, most patients still do not show an effective therapeutic response against ICBs, which may be related to local immunosuppression of the tumor.146 Inhibitors of ubiquitinase/deubiquitinase can modulate the tumor microenvironment and improve the sensitivity of tumors to T-cell killing, and their combination with ICB has been shown to significantly improve the therapeutic efficacy of ICB.147,148 Therefore, the combination of drugs can improve ICB drug resistance and enhance the efficacy of tumor treatment.

Firstly, E3 ubiquitin ligase inhibitors may improve the efficacy of ICB therapy. Inhibitory apoptosis proteins (IAPs) are a group of E3 ubiquitin ligases that include eight members: cIAP1, cIAP2, NAIP, Survivin, XIAP, Bruce, ILP-2, and Livin.149 Abnormally high expression of IAPs is a common oncogenic event in human cancers, and IAPs block cystatinase-mediated apoptosis by binding to and ubiquitinating degraded cystatinases.149, 150, 151 Various IAP inhibitors such as LCL161, Debio1143, and birinapant have been developed and found to be effective in inhibiting cancer.152, 153, 154 The IAP inhibitor ASTX660 sensitized a mouse model of head and neck squamous cell carcinoma to tumor necrosis factor alpha (TNF-α) and sensitized tumor cells to perforin/granzyme B, TNF-α, TRAIL, and FasL-mediated antigen-specific T-cell killing, but did not damage the host, and its combination with PD-1 antibody showed enhanced antitumor activity, thereby significantly delaying or eradicate tumors.155 The IAP inhibitor birinapant makes tumor cells more sensitive to CL-derived TNF killing, while TNF is elevated after PD-1 blockade, and the combination of the two further enhances the efficacy of anti-PD-1 antibody therapy.156 Another IAP inhibitor, LCL161, modulates the tumor microenvironment of multiple myeloma and induces strong immune activation, thereby stimulating anti-tumor phagocytic activity and durable anti-tumor immunity; when combined with LCL161 and PD-1 antibody, it significantly enhances anti-PD-1 antibody efficacy.157 In addition to enhancing the efficacy of anti-PD-1 therapy, IAP inhibitors can also be combined with anti-cytotoxic T-lymphocyte antigen 4 to induce tumor cell sensitivity to killing. LCL161 sensitizes tumors to TNF-α-induced killing, enhances cytotoxic T lymphocyte activity against tumors, and promotes therapeutic efficacy in glioblastoma in combination with anti-cytotoxic T-lymphocyte antigen 4, and similar results have been found in other cancers such as breast cancer.158 MDM2 is one of the E3 ubiquitin ligases that binds to the tumor suppressor p53 and mediates the ubiquitinated degradation of p53, and overexpression of MDM2 is a factor in the poor prognosis of various tumors.120,159 In recent years, several MDM2 inhibitors have been found that can be combined with ICB to improve the tumor treatment effect of ICB. Instead of working by degrading MDM2, these inhibitors inhibit MDM2-mediated p53 ubiquitination by blocking the binding of MDM2 to p53.69,148 AMG232 is an investigational orally bioavailable selective MDM2 inhibitor, and the combination of AMG232 and pembrolizumab anti-PD-1 treatment reduces IL-6 expression as well as enhances T cell-mediated tumor killing in ovarian cancer cell lines.69 APG-115 inhibits the interaction between MDM2 and p53, which promotes the activation of p53 in tumor microenvironment immune cells, resulting in increased infiltration of CD8+ T cells and M1 macrophages while reduced infiltration of M2 macrophages, enhancing the anti-PD-1 antibody anti-tumor immune efficacy.148 Similarly, HDM201, an MDM2 inhibitor, inhibited the ubiquitinated degradation of p53 by MDM2, increased dendritic cells as well as the CD8+/Treg ratio, promoted a durable tumor-specific immune memory response and improved the anti-tumor response of anti-PD-L1 antibody/anti-PD-1 antibody against colon cancer.160 In addition to E3 ubiquitin ligases, deubiquitinases can also influence the efficacy of ICB therapy. USP7 is one of the most studied deubiquitinases and plays a critical role in mediating MDM2 stabilization, and the combination of USP7 inhibitors with ICB was also found to improve therapeutic efficacy. P5091 is a USP7 inhibitor that inhibits Treg activity and preserves key T effector cell function in a mouse lung cancer model. P5091 promotes anti-tumor immunity and its activity is significantly increased in combination with anti-PD-1 antibodies.161

There have been several clinical trials on the combination of ubiquitinase and ICB, further improving the understanding of their combined use. A clinical Ib study in patients with metastatic solid tumors found that APG-115 in combination with pembrolizumab was well tolerated and its promising anti-tumor effects have been seen in several tumor types.162 Meanwhile, most clinical trials are still ongoing, such as APG-115 in patients with advanced solid tumors or lymphoma (NCT02935907), PDR001 in combination with LCL161, everolimus, or panobinostat (NCT02890069), multiple immunotherapy-based therapeutic combinations in patients with metastatic colorectal cancer (Morpheus-CRC) (NCT03555149), atezolizumab and cobimetinib or idasanutlin in participants with stage IV or unresectable recurrent estrogen receptor positive breast cancer (NCT03566485), and birinapant and pembrolizumab in solid tumors in a dose escalation study (NCT02587962). The subsequent results of these studies will be beneficial in increasing our knowledge of the combination. Therefore, the combination of ubiquitinase/deubiquitinase and ICB is a promising way to improve treatment resistance and enhance the efficacy of tumor immunotherapy.

Combined application of ubiquitinase/deubiquitinase inhibitors and cancer vaccines

Prophylactic and therapeutic vaccines are representative strategies for cancer immunotherapy. The former aims to induce immune memory by administering vaccines to healthy individuals to prevent the onset of disease caused by specific cancers. The latter is used for disease management in cancer patients by boosting or activating the patient's own immune system. Cancer vaccines can be classified into three main categories based on the technology and content they use, namely cellular vaccines (tumor or immune cells), protein/peptide vaccines, and nucleic acid vaccines (DNA, RNA, or viral vectors).163 Until now, the most used vaccine is a preventive vaccine against human papillomavirus-related cervical cancer.164 Currently, except for some specific cancer vaccines, monotherapies using cancer vaccines usually have only minimal clinical effect. The lower efficacy of monotherapy may be caused by multiple immune evasion mechanisms in cancer, with the immunosuppressive tumor microenvironment playing an important role.163,165

For E3 ubiquitin ligase inhibitors, several studies have demonstrated that they can influence tumor vaccine therapy. The MDM2 inhibitor Nutlin-3 can block the interaction between MDM2 and p53. This maintains the stability of p53 thereby increasing tumor HLA class I expression via endoplasmic reticulum aminopeptidase 1121 up-regulation of tumor HLA expression and enhance the anti-tumor response of MDM2-specific T cells, which can effectively promote MDM232-46 peptide vaccine-induced T cell killing of tumor cells.120 In addition, the IAP inhibitor M1 enhances the response of CD4+ CD8+ T cells, and other anti-tumor effector cells and the combination with B16 vaccines (GVAX) improves the efficacy of tumor vaccines.166 Smac mimetic, an inhibitor of IAP2 and XIAP, acts through TNF-α secreted by BCG-stimulated neutrophils to promote BCG-induced killing of tumor cells, and the combination of the two drugs effectively promotes the treatment of bladder cancer.167 For deubiquitinating enzyme inhibitors, in a study of a mouse lung cancer model, it was found that the combination of USP7 inhibitor P5091 and adenovirus vaccine significantly increased infiltration of tumor-specific CD8+ T cells and IFN-γ production with reduced accumulation of Foxp3+ Treg cells in the tumor, resulting in a significant limitation of tumor growth.161 In conclusion, the combination of tumor vaccines with ubiquitinase/deubiquitinase inhibitors has a greater therapeutic potential, but more studies are still needed to determine the specific mechanisms and effects.

Combined application of ubiquitinase/deubiquitinase inhibitors and CAR-T

CAR-T cell therapies have been proven successful in treating hematologic malignancies, particularly acute lymphoblastic leukemia and B-cell lymphoma, and the FDA has approved five CAR-T therapies for hematologic malignancies.168 However, the poor efficacy of CAR-T cells in solid tumors may be due to tumor-associated immunosuppression. Some of the major barriers to CAR immunotherapy in solid tumors include CAR-T cell manufacturing, lack of tumor-specific antigens, inefficient CAR-T lymphocyte transport and infiltration of tumor sites, immunosuppressive tumor microenvironment, treatment-related toxicity, and antigen escape.168,169 As an antagonist of IAP, birinapant inhibits IAP to sensitize tumor cells to CAR-T cell-derived TNF and significantly enhances the anti-tumor activity of CAR-T lymphocyte therapy in vitro and in vivo. Combining CAR-T cell therapy with birinapant significantly inhibits tumor growth in mice in vivo, with stronger therapeutic effects than treatment alone.169 CAR-T therapy is less durable because CARs are susceptible to degradation by ubiquitination. It was found that the ubiquitination of CAR could be blocked by mutating all cytoplasmic lysine to arginine, and such cells were called retrievable CAR-T cells. Such recyclable CAR-T cells have been shown to have better long-term killing capacity, better durability, and enhanced anti-tumor capabilities.113

In conclusion, studies have shown that the modulation of the ubiquitination pathway in combination with CAR-T cells can improve the efficacy of solid malignant tumor overt cell therapy, providing a new idea for improving CAR-T cell therapy.

Combined application of ubiquitinase/deubiquitinase inhibitors and anti-tumor antibodies

Nowadays, the immunotherapy of cancer is rapidly developing, among which anti-tumor antibodies are a therapeutic strategy that cannot be ignored. Monoclonal antibodies for tumor treatment are mainly based on three mechanisms: (i) the inhibition of factors and receptors that activate signaling pathways in cancer cell division and angiogenesis through antibody binding; (ii) the antibody-dependent cellular cytotoxicity (ADCC) such as rituximab, transtuzumab, cetuximab, and pertuzumab; (iii) complement-dependent cytotoxicity such as rituximab, alemtuzumab, cetuximab, and ofatumumab.170, 171, 172 The main types of cancers targeted by monoclonal antibodies are breast cancer, colon cancer, lymphoma, etc.173

ADCC is a key mechanism for the anti-tumor effects of clinically applied anti-tumor antibodies. It was found that the ADCC therapeutic effect of anti-tumor monoclonal antibodies was facilitated by increasing the number and activity of natural killer cells.174 It is possible that the ubiquitin-proteasome pathway could have an influence on ADCC by regulating natural killer cells, which in turn could improve therapeutic efficacy. The E3 ubiquitin ligase CRBN complex facilitates the ubiquitination degradation of IKZF1/3, thereby rescuing the inhibition of IKZF1/3 on natural killer cells. Well, this process can be facilitated by the immunomodulatory drug pomalidomide and enhances the ADCC effect.175 Thus, the ubiquitinated proteasome pathway may serve as a potential target in modulating ADCC effects and promoting the efficacy of anti-tumor monoclonal antibody therapy. Also, the NF-κB signaling pathway plays an important role in tumor immunity and is also closely related to the efficacy of monoclonal antibody therapy.74,176 The ubiquitinated proteasome pathway can influence the therapeutic efficacy of monoclonal antibodies by regulating NF-κB. Trastuzumab is a commonly used anti-tumor monoclonal antibody, but the immunosuppressive microenvironment of tumors promotes drug resistance to trastuzumab and hampers therapeutic efficacy. TRAF6/3 acts as an E3 ubiquitin ligase and induces its proteasomal degradation through k48-linked self-ubiquitination, thereby inhibiting NF-κB signaling and promoting drug resistance in tumors. Whereas targeting CD40 inhibits ubiquitination of TRAF6/3, and drug resistance is overcome by treatment with anti-CD40-scFv-linked anti-HER2 (CD40 × HER2) bispecific antibody (bsAb).177 In addition to this, brentuximab vedotin (BV), a drug-coupled anti-CD30 antibody, is one of the most effective therapeutic agents for patients with refractory/recurrent Hodgkin's lymphoma, but there are still many instances of therapy resistance to brentuximab vedotin. Ubiquitin editing enzyme A20 down-regulates TNF-α-induced NF-κB signaling by catalyzing ubiquitination of receptor-interacting protein and negatively regulates the activity of NF-κB, and thus up-regulates brentuximab vedotin sensitivity.176,178

A recent study found that the USP1 inhibitor pimozide inhibited the deubiquitination of MAX/MYC proteins by USP1, induced apoptosis, autophagy, and cell cycle arrest in tumor cells, and improved rituximab treatment of diffuse large B-cell lymphoma resistance.179 This provides new insights into the use of ubiquitinase/deubiquitinase inhibitors in combination with anti-tumor antibodies, suggesting that this may be another way to improve the efficacy of tumor therapy.

Conclusion

Ovarian cancer is one of the deadliest gynecologic malignancies in the world, with a 5-year survival rate of less than 50%, and despite multiple treatment options today, it has not been effective in improving overall survival rates.180 Ubiquitination and deubiquitination are important post-translational modification mechanisms that regulate the tumor microenvironment and host immune response to tumor cells, and they also play a key role in regulating the proliferation, migration, and invasion of ovarian cancer cells.18,180 In addition, other post-translational modifications such as phosphorylation and acetylation were found to regulate ovarian carcinogenesis together with ubiquitination/deubiquitination. For example, Gα13 is involved in cell proliferation, migration, and invasion, regulates large tumor suppressor kinase phosphorylation at serine 909 upon activation, and induces the recruitment of the itchy E3 ubiquitin ligase to trigger large tumor suppressor kinase 1 degradation. Large tumor suppressor kinase 1 is a key component of the Hippo signaling pathway, and its down-regulation promotes epithelial–mesenchymal transition in ovarian cancer epithelial cells, resulting in enhanced invasiveness.181 Lysine acetyltransferase 6 A is a MYST-type histone acetyltransferase. It binds to and acetylates COP1 at K294, which impairs the function of COP1 as an E3 ubiquitin ligase and leads to the accumulation and enhanced activity of β-catenin, thereby promoting the proliferation and migratory ability of ovarian cancer cells.182 Therefore, the combination of multiple post-translational modifications and ubiquitination/deubiquitination may be a potential new target for ovarian cancer therapy.

Studies have shown that ubiquitinase/deubiquitinase can be involved in cancer therapy as a target, and most studies have focused on IAP and MDM2 inhibitors, for example, the IAP inhibitor birinapant has been shown to be well tolerated in clinical trials with stable anti-tumor activity in some patients with solid tumors.162 Another phase I clinical trial also demonstrated that the MDM2 inhibitor ALRN-6924 was well tolerated and showed anti-tumor activity in patients with solid tumors and lymphomas carrying TP53.183 Further studies have found that ubiquitinase/deubiquitinase inhibitors can be used in combination with a variety of known immunotherapies to improve efficacy, including ICB, CAR-T cell therapy, tumor vaccines, and anti-tumor antibodies.184 Of these, anti-PD-1 therapy is the most intensively studied, with several clinical trials already underway.148,160

Although there is extensive research on cancer immunotherapy, on the one hand, the use of ubiquitinase/deubiquitinase as a target in combination with classical immunotherapeutic approaches in ovarian cancer is still inadequate, and on the other hand, there is a lack of sufficient clinical trials to drive research progress. In conclusion, research on the combination of ubiquitinase/deubiquitinase inhibitors with immunotherapy may provide more possibilities for improving the treatment of ovarian cancer in the future.

Author contributions

Ting Sun and Liwei Ma conceived the structure of the manuscript and revised the manuscript. Huiling Guo and Jianwei Wei collected the related paper and drafted the manuscript. Yuyan Zhang and Junhu Wan created the figures. Weiwei Wang, Ling Gao, and Jiajing Li revised this manuscript. All authors read and approved the final manuscript.

Conflict of interests

These authors declare that they have no competing interests.

Funding

This project was supported by the 10.13039/501100001809 National Natural Science Foundation of China (No. 82002751 ), the Medical Science and Technology Project of Henan Province, China (No. SBGJ202102139 ), 10.13039/501100002858 China Postdoctoral Science Foundation (No. 2020M682361 ), Excellent Youth Foundation of Henan Province, China (No. 222300420071 ), Outstanding Young Talents of Health Science and Technology Innovation of Henan Province, China (No. YXKC2022033 ), and the Funding for Scientific Research and Innovation Team of The First Affiliated Hospital of Zhengzhou University, Henan, China (No. QNCXTD2023005 ).

Peer review under responsibility of Chongqing Medical University.
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References

1 Wang Z. Guo E. Yang B. Trends and age-period-cohort effects on mortality of the three major gynecologic cancers in China from 1990 to 2019: cervical, ovarian and uterine cancer Gynecol Oncol 163 2 2021 358 363 34507827
2 Sung H. Ferlay J. Siegel R.L. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries CA A Cancer J Clin 71 3 2021 209 249
3 Green D.S. Ning F. Duemler A. Intraperitoneal monocytes plus IFNs as a novel cellular immunotherapy for ovarian cancer: mechanistic characterization and results from a phase I clinical trial [published correction appears in Clin Cancer Res. 2023 Jan 17;29(2):501] Clin Cancer Res 29 2 2023 349 363 36099324
4 Yang C. Xia B.R. Zhang Z.C. Zhang Y.J. Lou G. Jin W.L. Immunotherapy for ovarian cancer: adjuvant, combination, and neoadjuvant Front Immunol 11 2020 577869
5 Lee S.M. Lee S. Cho H.W. Application of immune checkpoint inhibitors in gynecological cancers: what do gynecologists need to know before using immune checkpoint inhibitors? Int J Mol Sci 24 2 2023 974 36674491
6 Schossig P. Coskun E. Arsenic R. Target selection for T-cell therapy in epithelial ovarian cancer: systematic prioritization of self-antigens Int J Mol Sci 24 3 2023 2292 36768616
7 Shen Y. Liu G. Zhang Q. Tian X. Ouyang L. Zhang L. Construction of CAR-T cells targeting TM4SF1 and its anti-tumor capacity in ovarian cancer Immunol Lett 255 2023 1 9 36739093
8 Morand S. Devanaboyina M. Staats H. Stanbery L. Nemunaitis J. Ovarian cancer immunotherapy and personalized medicine Int J Mol Sci 22 12 2021 6532 34207103
9 Rajtak A. Ostrowska-Leśko M. Żak K. Tarkowski R. Kotarski J. Okła K. Integration of local and systemic immunity in ovarian cancer: implications for immunotherapy Front Immunol 13 2022 1018256
10 Liu Y.C. Ubiquitin ligases and the immune response Annu Rev Immunol 22 2004 81 127 15032575
11 Han S. Wang R. Zhang Y. The role of ubiquitination and deubiquitination in tumor invasion and metastasis Int J Biol Sci 18 6 2022 2292 2303 35414786
12 Hershko A. Ciechanover A. The ubiquitin system Annu Rev Biochem 67 1998 425 479 9759494
13 Wang Z. Liu P. Inuzuka H. Wei W. Roles of F-box proteins in cancer Nat Rev Cancer 14 4 2014 233 247 24658274
14 Ji M. Zhao Z. Li Y. FBXO6-mediated RNASET2 ubiquitination and degradation governs the development of ovarian cancer Cell Death Dis 12 4 2021 317 33767133
15 Ji J. Shen J. Xu Y. FBXO2 targets glycosylated SUN2 for ubiquitination and degradation to promote ovarian cancer development Cell Death Dis 13 5 2022 442 35525855
16 Li X. Yang K.B. Chen W. CUL3 (cullin 3)-mediated ubiquitination and degradation of BECN1 (beclin 1) inhibit autophagy and promote tumor progression Autophagy 17 12 2021 4323 4340 33977871
17 Ji M. Zhao Z. Li Y. FBXO16-mediated hnRNPL ubiquitination and degradation plays a tumor suppressor role in ovarian cancer Cell Death Dis 12 8 2021 758 34333526
18 Sun T. Liu Z. Bi F. Yang Q. Deubiquitinase PSMD14 promotes ovarian cancer progression by decreasing enzymatic activity of PKM2 Mol Oncol 15 12 2021 3639 3658 34382324
19 Wang X. Tokheim C. Gu S.S. In vivo CRISPR screens identify the E3 ligase Cop1 as a modulator of macrophage infiltration and cancer immunotherapy target Cell 184 21 2021 5357 5374.e22 34582788
20 Hu X. Wang J. Chu M. Liu Y. Wang Z.W. Zhu X. Emerging role of ubiquitination in the regulation of PD-1/PD-L1 in cancer immunotherapy Mol Ther 29 3 2021 908 919 33388422
21 Song M. Yeku O.O. Rafiq S. Tumor derived UBR5 promotes ovarian cancer growth and metastasis through inducing immunosuppressive macrophages Nat Commun 11 1 2020 6298 33293516
22 Matsuura K. Huang N.J. Cocce K. Zhang L. Kornbluth S. Downregulation of the proapoptotic protein MOAP-1 by the UBR5 ubiquitin ligase and its role in ovarian cancer resistance to cisplatin Oncogene 36 12 2017 1698 1706 27721409
23 Zhang Q. Wang W. Gao Q. β-TRCP-mediated AEBP2 ubiquitination and destruction controls cisplatin resistance in ovarian cancer Biochem Biophys Res Commun 523 1 2020 274 279 31864706
24 Wu A.Y. Gu L.Y. Cang W. Fn14 overcomes cisplatin resistance of high-grade serous ovarian cancer by promoting Mdm2-mediated p53-R248Q ubiquitination and degradation J Exp Clin Cancer Res 38 1 2019 176 31023317
25 Chen L. Gao W. Sha C. SIAH1-mediated RPS3 ubiquitination contributes to chemosensitivity in epithelial ovarian cancer Aging (Albany NY) 14 15 2022 6202 6226 35951361
26 Swatek K.N. Komander D. Ubiquitin modifications Cell Res 26 4 2016 399 422 27012465
27 Chau V. Tobias J.W. Bachmair A. A multiubiquitin chain is confined to specific lysine in a targeted short-lived protein Science 243 4898 1989 1576 1583 2538923
28 Ciechanover A. The ubiquitin-proteasome proteolytic pathway Cell 79 1 1994 13 21 7923371
29 Kirisako T. Kamei K. Murata S. A ubiquitin ligase complex assembles linear polyubiquitin chains EMBO J 25 20 2006 4877 4887 17006537
30 Buneeva O. Medvedev A. Atypical ubiquitination and Parkinson's disease Int J Mol Sci 23 7 2022 3705 35409068
31 Park J. Cho J. Song E.J. Ubiquitin-proteasome system (UPS) as a target for anticancer treatment Arch Pharm Res (Seoul) 43 11 2020 1144 1161
32 Clague M.J. Barsukov I. Coulson J.M. Liu H. Rigden D.J. Urbé S. Deubiquitylases from genes to organism Physiol Rev 93 3 2013 1289 1315 23899565
33 Yuan T. Yan F. Ying M. Inhibition of ubiquitin-specific proteases as a novel anticancer therapeutic strategy Front Pharmacol 9 2018 1080 30319415
34 Mevissen T.E.T. Komander D. Mechanisms of deubiquitinase specificity and regulation Annu Rev Biochem 86 2017 159 192 28498721
35 Du J. Fu L. Sui Y. Zhang L. The function and regulation of OTU deubiquitinases Front Med 14 5 2020 542 563 31884527
36 Jiang Y. Wang C. Zhou S. Targeting tumor microenvironment in ovarian cancer: premise and promise Biochim Biophys Acta Rev Cancer 1873 2 2020 188361
37 Yu T. Gan S. Zhu Q. Modulation of M2 macrophage polarization by the crosstalk between Stat6 and Trim24 Nat Commun 10 1 2019 4353 31554795
38 Pan Z. Zhao R. Li B. EWSR1-induced circNEIL3 promotes glioma progression and exosome-mediated macrophage immunosuppressive polarization via stabilizing IGF2BP3 Mol Cancer 21 1 2022 16 35031058
39 Li B. Zhu L. Lu C. circNDUFB2 inhibits non-small cell lung cancer progression via destabilizing IGF2BPs and activating anti-tumor immunity Nat Commun 12 1 2021 295 33436560
40 Zhang P. Su T. Zhang S. Comprehensive analysis of prognostic value of MEX3A and its relationship with immune infiltrates in ovarian cancer J Immunol Res 2021 2021 5574176
41 Li B. Qi Z.P. He D.L. NLRP7 deubiquitination by USP10 promotes tumor progression and tumor-associated macrophage polarization in colorectal cancer J Exp Clin Cancer Res 40 1 2021 126 33838681
42 Cortez J.T. Montauti E. Shifrut E. CRISPR screen in regulatory T cells reveals modulators of Foxp3 Nature 582 7812 2020 416 420 32499641
43 Montauti E. Weinberg S.E. Chu P. A deubiquitination module essential for Treg fitness in the tumor microenvironment Sci Adv 8 47 2022 eabo4116
44 Chen B. Sang Y. Song X. Exosomal miR-500a-5p derived from cancer-associated fibroblasts promotes breast cancer cell proliferation and metastasis through targeting USP28 Theranostics 11 8 2021 3932 3947 33664871
45 Bai J. Liu T. Tu B. Autophagy loss impedes cancer-associated fibroblast activation via downregulating proline biosynthesis Autophagy 19 2 2023 632 643 35786294
46 Zhang H. Deng T. Liu R. CAF secreted miR-522 suppresses ferroptosis and promotes acquired chemo-resistance in gastric cancer Mol Cancer 19 1 2020 43 32106859
47 Chen B. Zhu H.Y. Yang B. Cao J. The dichotomous role of immunoproteasome in cancer: friend or foe? Acta Pharm Sin B 13 2022 1976 1989 37250147
48 Dong J. Miao J. Miao Y. Small molecule degraders of protein tyrosine phosphatase 1B and T-cell protein tyrosine phosphatase for cancer immunotherapy Angew Chem Int Ed Engl 62 22 2023 e202303818
49 Kasuga Y. Ouda R. Watanabe M. FBXO11 constitutes a major negative regulator of MHC class II through ubiquitin-dependent proteasomal degradation of CIITA Proc Natl Acad Sci U S A 120 24 2023 e2218955120
50 Mamrosh J.L. Sherman D.J. Cohen J.R. Quantitative measurement of the requirement of diverse protein degradation pathways in MHC class I peptide presentation Sci Adv 9 25 2023 eade7890
51 Chen X. Lu Q. Zhou H. A membrane-associated MHC-I inhibitory axis for cancer immune evasion Cell 186 18 2023 3903 3920.e21 37557169
52 Wilson K.R. Jenika D. Blum A.B. MHC class II ubiquitination regulates dendritic cell function and immunity J Immunol 207 9 2021 2255 2264 34599081
53 Wilson K.R. Liu H. Healey G. MARCH1-mediated ubiquitination of MHC II impacts the MHC I antigen presentation pathway PLoS One 13 7 2018 e0200540
54 Takahashi M. Lio C.W.J. Campeau A. The tumor suppressor kinase DAPK3 drives tumor-intrinsic immunity through the STING-IFN-β pathway Nat Immunol 22 4 2021 485 496 33767426
55 Li J.Y. Zhao Y. Gong S. TRIM21 inhibits irradiation-induced mitochondrial DNA release and impairs antitumour immunity in nasopharyngeal carcinoma tumour models Nat Commun 14 2023 865 36797289
56 Ghosh M. Saha S. Li J. Montrose D.C. Martinez L.A. p53 engages the cGAS/STING cytosolic DNA sensing pathway for tumor suppression Mol Cell 83 2 2023 266 280.e6 36638783
57 Apriamashvili G. Vredevoogd D.W. Krijgsman O. Ubiquitin ligase STUB1 destabilizes IFNγ-receptor complex to suppress tumor IFNγ signaling Nat Commun 13 1 2022 1923 35395848
58 Cassidy K.B. Bang S. Kurokawa M. Gerber S.A. Direct regulation of Chk1 protein stability by E3 ubiquitin ligase HUWE1 FEBS J 287 10 2020 1985 1999 31713291
59 Shearer R.F. Typas D. Coscia F. K27-linked ubiquitylation promotes p97 substrate processing and is essential for cell proliferation EMBO J 41 9 2022 e110145
60 Chen S. Liu Y. Zhou H. Advances in the development ubiquitin-specific peptidase (USP) inhibitors Int J Mol Sci 22 9 2021 4546 33925279
61 Ye Z. Chen J. Huang P. Xuan Z. Zheng S. Ubiquitin-specific peptidase 10, a deubiquitinating enzyme: assessing its role in tumor prognosis and immune response Front Oncol 12 2022 990195
62 Topalian S.L. Taube J.M. Pardoll D.M. Neoadjuvant checkpoint blockade for cancer immunotherapy Science 367 6477 2020 eaax0182
63 Hayashi H. Nakagawa K. Combination therapy with PD-1 or PD-L1 inhibitors for cancer Int J Clin Oncol 25 5 2020 818 830 31549270
64 Sivori S. Vacca P. Del Zotto G. Munari E. Mingari M.C. Moretta L. Human NK cells: surface receptors, inhibitory checkpoints, and translational applications Cell Mol Immunol 16 5 2019 430 441 30778167
65 Gato-Cañas M. Zuazo M. Arasanz H. PDL1 signals through conserved sequence motifs to overcome interferon-mediated cytotoxicity Cell Rep 20 8 2017 1818 1829 28834746
66 Brahmer J.R. Tykodi S.S. Chow L.Q.M. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer N Engl J Med 366 26 2012 2455 2465 22658128
67 Huang L.J. Deng X.F. Chang F. Wu X.L. Wu Y. Diao Q.Z. Prognostic significance of programmed cell death ligand 1 expression in patients with ovarian carcinoma: a systematic review and meta-analysis Medicine (Baltim) 97 43 2018 e12858
68 Kornepati A.V.R. Vadlamudi R.K. Curiel T.J. Programmed death ligand 1 signals in cancer cells Nat Rev Cancer 22 3 2022 174 189 35031777
69 Sahin I. Zhang S. Navaraj A. Correction: AMG-232 sensitizes high MDM2-expressing tumor cells to T-cell-mediated killing Cell Death Dis 6 2020 71
70 Wang Z. Kang W. Li O. Abrogation of USP7 is an alternative strategy to downregulate PD-L1 and sensitize gastric cancer cells to T cells killing Acta Pharm Sin B 11 3 2021 694 707 33777676
71 De S. Holvey-Bates E.G. Mahen K. Willard B. Stark G.R. The ubiquitin E3 ligase FBXO22 degrades PD-L1 and sensitizes cancer cells to DNA damage Proc Natl Acad Sci U S A 118 47 2021 e2112674118
72 Murray C. Galvan E. Ontiveros C. Pharmacologic tumor PDL1 depletion with cefepime or ceftazidime promotes DNA damage and sensitivity to DNA-damaging agents Int J Mol Sci 23 9 2022 5129 35563520
73 Bai H. Padron A.S. Deng Y. Pharmacological tumor PDL1 depletion with chlorambucil treats ovarian cancer and melanoma: improves antitumor immunity and renders anti-PDL1-resistant tumors anti-PDL1-sensitive through NK cell effects J Immunother Cancer 11 2 2023 e004871
74 Decout A. Katz J.D. Venkatraman S. Ablasser A. The cGAS-STING pathway as a therapeutic target in inflammatory diseases Nat Rev Immunol 21 9 2021 548 569 33833439
75 Zhai L. Spranger S. Binder D.C. Molecular pathways: targeting Ido1 and other tryptophan dioxygenases for cancer immunotherapy Clin Cancer Res 21 24 2015 5427 5433 26519060
76 Zhai L. Ladomersky E. Lenzen A. Ido1 in cancer: a Gemini of immune checkpoints Cell Mol Immunol 15 5 2018 447 457 29375124
77 Liu M. Wang X. Wang L. Targeting the Ido1 pathway in cancer: from bench to bedside J Hematol Oncol 11 1 2018 100 30068361
78 Feng X. Tang R. Zhang R. A comprehensive analysis of Ido1 expression with tumour-infiltrating immune cells and mutation burden in gynaecologic and breast cancers J Cell Mol Med 24 9 2020 5238 5248 32227579
79 Grobben Y. de Man J. van Doornmalen A.M. Targeting indoleamine 2,3-dioxygenase in cancer models using the novel small molecule inhibitor NTRC 3883-0 Front Immunol 11 2020 609490
80 Odunsi K. Qian F. Lugade A.A. Metabolic adaptation of ovarian tumors in patients treated with an Ido1 inhibitor constrains antitumor immune responses Sci Transl Med 14 636 2022 eabg8402
81 Shi D. Wu X. Jian Y. USP14 promotes tryptophan metabolism and immune suppression by stabilizing Ido1 in colorectal cancer Nat Commun 13 1 2022 5644 36163134
82 Choschzick M. Hantaredja W. Tennstedt P. Gieseking F. Wölber L. Simon R. Role of TP53 mutations in vulvar carcinomas Int J Gynecol Pathol 30 5 2011 497 504 21804386
83 Amaral J.D. Xavier J.M. Steer C.J. Rodrigues C.M. The role of p53 in apoptosis Discov Med 9 45 2010 145 152 20193641
84 Nijman H.W. Lambeck A. van der Burg S.H. van der Zee A.G. Daemen T. Immunologic aspect of ovarian cancer and p53 as tumor antigen J Transl Med 3 2005 34 16164749
85 Cancer Genome Atlas Research Network Integrated genomic analyses of ovarian carcinoma [published correction appears in Nature. 2012 Oct 11;490(7419):298] Nature 474 7353 2011 609 615 21720365
86 Shih IeM. Kurman R.J. Ovarian tumorigenesis: a proposed model based on morphological and molecular genetic analysis Am J Pathol 164 5 2004 1511 1518 15111296
87 Mielczarek-Palacz A. Sikora J. Kondera-Anasz Z. The immune complex p53 protein/anti-p53 autoantibodies in the pathogenesis of ovarian serous carcinoma Ginekol Pol 91 9 2020 519 253 33030731
88 Goodell V. Salazar L.G. Urban N. Antibody immunity to the p53 oncogenic protein is a prognostic indicator in ovarian cancer J Clin Oncol 24 5 2006 762 768 16391298
89 Lambeck A. Leffers N. Hoogeboom B.N. P53-specific T cell responses in patients with malignant and benign ovarian tumors: implications for p53 based immunotherapy Int J Cancer 121 3 2007 606 614 17415711
90 El-Arabey A.A. Abdalla M. SnapShot Abd-Allah AR. TP53 status and macrophages infiltration in TCGA-analyzed tumors Int Immunopharm 86 2020 106758
91 Hardwick N.R. Frankel P. Ruel C. p53-reactive T cells are associated with clinical benefit in patients with platinum-resistant epithelial ovarian cancer after treatment with a p53 vaccine and gemcitabine chemotherapy Clin Cancer Res 24 6 2018 1315 1325 29301826
92 Leffers N. Lambeck A.J.A. Gooden M.J.M. Immunization with a P53 synthetic long peptide vaccine induces P53-specific immune responses in ovarian cancer patients, a phase II trial Int J Cancer 125 9 2009 2104 2113 19621448
93 Vermeij R. Leffers N. Hoogeboom B.N. Potentiation of a p53-SLP vaccine by cyclophosphamide in ovarian cancer: a single-arm phase II study Int J Cancer 131 5 2012 E670 E680 22139992
94 Dijkgraaf E.M. Santegoets S.J. Reyners A.K. A phase 1/2 study combining gemcitabine, Pegintron and p53 SLP vaccine in patients with platinum-resistant ovarian cancer Oncotarget 6 31 2015 32228 32243 26334096
95 Zhou M. Cheng H. Fu Y. Zhang J. Long noncoding RNA DARS-AS1 regulates TP53 ubiquitination and affects ovarian cancer progression by modulation miR-194-5p/RBX1 axis J Biochem Mol Toxicol 35 10 2021 e22865
96 Min X. Zhang T. Lin Y. Wang B. Zhu K. Metformin inhibits the growth of ovarian cancer cells by promoting the Parkin-induced p53 ubiquitination Biosci Rep 2020 BSR20200679
97 Zhang L. Jin Y. Yang H. SMYD3 promotes epithelial ovarian cancer metastasis by downregulating p53 protein stability and promoting p53 ubiquitination Carcinogenesis 40 12 2019 1492 1503 31002112
98 Wang S. Hao Q. Li J. Ubiquitin ligase DTX3 empowers mutant p53 to promote ovarian cancer development Genes Dis 9 3 2022 705 716 35782979
99 Chen Y. Hao Q. Wang J. Ubiquitin ligase TRIM71 suppresses ovarian tumorigenesis by degrading mutant p53 Cell Death Dis 10 10 2019 737 31570706
100 Padmanabhan A. Candelaria N. Wong K.K. USP15-dependent lysosomal pathway controls p53-R175H turnover in ovarian cancer cells Nat Commun 9 1 2018 1270 29593334
101 Fucà G. Reppel L. Landoni E. Savoldo B. Dotti G. Enhancing chimeric antigen receptor T-cell efficacy in solid tumors Clin Cancer Res 26 11 2020 2444 2451 32015021
102 Rafiq S. Hackett C.S. Brentjens R.J. Engineering strategies to overcome the current roadblocks in CAR T cell therapy Nat Rev Clin Oncol 17 3 2020 147 167 31848460
103 Chen J. Hu J. Gu L. Anti-mesothelin CAR-T immunotherapy in patients with ovarian cancer Cancer Immunol Immunother 72 2 2023 409 425 35925286
104 Zhang Q. Liu G. Liu J. The antitumor capacity of mesothelin-CAR-T cells in targeting solid tumors in mice Mol Ther Oncolytics 20 2021 556 568 33738341
105 Zhang Y. Wang P. Wang T. Fang Y. Ding Y. Qian Q. Chimeric antigen receptor T cells engineered to secrete CD40 agonist antibodies enhance antitumor efficacy J Transl Med 19 1 2021 82 33602263
106 Liang Z. Dong J. Yang N. Tandem CAR-T cells targeting FOLR1 and MSLN enhance the antitumor effects in ovarian cancer Int J Biol Sci 17 15 2021 4365 4376 34803504
107 Shu R. Evtimov V.J. Hammett M.V. Engineered CAR-T cells targeting TAG-72 and CD47 in ovarian cancer Mol Ther Oncolytics 20 2021 325 341 33614914
108 Sánchez-Paulete A.R. Mateus-Tique J. Mollaoglu G. Targeting macrophages with CAR T cells delays solid tumor progression and enhances antitumor immunity Cancer Immunol Res 10 11 2022 1354 1369 36095236
109 Mabrouk N. Tran T. Sam I. CXCR6 expressing T cells: functions and role in the control of tumors Front Immunol 13 2022 1022136
110 Rodriguez-Garcia A. Lynn R.C. Poussin M. CAR-T cell-mediated depletion of immunosuppressive tumor-associated macrophages promotes endogenous antitumor immunity and augments adoptive immunotherapy Nat Commun 12 1 2021 877 33563975
111 Wang X. Cabrera F.G. Sharp K.L. Spencer D.M. Foster A.E. Bayle J.H. Engineering tolerance toward allogeneic CAR-T cells by regulation of MHC surface expression with human Herpes virus-8 proteins Mol Ther 29 2 2021 718 733 33554868
112 Kumar J. Kumar R. Kumar Singh A. Deletion of Cbl-b inhibits CD8+ T-cell exhaustion and promotes CAR T-cell function J Immunother Cancer 9 1 2021 e001688
113 Li W. Qiu S. Chen J. Chimeric antigen receptor designed to prevent ubiquitination and downregulation showed durable antitumor efficacy Immunity 53 2 2020 456 470.e6 32758419
114 Zhao Q. Jiang Y. Xiang S. Engineered TCR-T cell immunotherapy in anticancer precision medicine: pros and cons Front Immunol 12 2021 658753
115 Liu Q. Li J. Zheng H. Adoptive cellular immunotherapy for solid neoplasms beyond CAR-T Mol Cancer 22 1 2023 1 27 36597126
116 Baulu E. Gardet C. Chuvin N. Depil S. TCR-engineered T cell therapy in solid tumors: state of the art and perspectives Sci Adv 9 7 2023 eadf3700
117 Wu J.W.Y. Dand S. Doig L. T-cell receptor therapy in the treatment of ovarian cancer: a mini review Front Immunol 12 2021 672502
118 van Amerongen R.A. Tuit S. Wouters A.K. PRAME and CTCFL-reactive TCRs for the treatment of ovarian cancer Front Immunol 14 2023 1121973
119 Montesion M. Murugesan K. Jin D.X. Somatic HLA class I loss is a widespread mechanism of immune evasion which refines the use of tumor mutational burden as a biomarker of checkpoint inhibitor response Cancer Discov 11 2 2021 282 292 33127846
120 Kono M. Kumai T. Hayashi R. Interruption of MDM2 signaling augments MDM2-targeted T cell-based antitumor immunotherapy through antigen-presenting machinery Cancer Immunol Immunother 70 12 2021 3421 3434 33866408
121 Wang B. Niu D. Lai L. Ren E.C. p53 increases MHC class I expression by upregulating the endoplasmic reticulum aminopeptidase ERAP1 Nat Commun 4 2013 2359 23965983
122 Pai S.G. Carneiro B.A. Mota J.M. Wnt/beta-catenin pathway: modulating anticancer immune response J Hematol Oncol 10 1 2017 101 28476164
123 Nguyen V.H.L. Hough R. Bernaudo S. Peng C. Wnt/β-catenin signalling in ovarian cancer: insights into its hyperactivation and function in tumorigenesis J Ovarian Res 12 1 2019 122 31829231
124 Zhong Z. Sepramaniam S. Chew X.H. PORCN inhibition synergizes with PI3K/mTOR inhibition in Wnt-addicted cancers Oncogene 38 40 2019 6662 6677 31391551
125 Cho A.R. Sul H.J. Kim Y.J. Kim B. Zang D.Y. RNF43 R117fs mutant positively regulates Wnt/β-catenin signaling by failing to internalize FZD expressed on the cell surface Sci Rep 12 1 2022 7013 35487932
126 Liu J. Xiao Q. Xiao J. Wnt/β-catenin signalling: function, biological mechanisms, and therapeutic opportunities Signal Transduct Targeted Ther 7 1 2022 3
127 Mao B. Wu W. Li Y. LDL-receptor-related protein 6 is a receptor for Dickkopf proteins Nature 411 6835 2001 321 325 11357136
128 Galon J. Bruni D. Approaches to treat immune hot, altered and cold tumours with combination immunotherapies Nat Rev Drug Discov 18 3 2019 197 218 30610226
129 Betella I. Turbitt W.J. Szul T. Wnt signaling modulator DKK1 as an immunotherapeutic target in ovarian cancer Gynecol Oncol 157 3 2020 765 774 32192732
130 Doo D.W. Meza-Perez S. Londoño A.I. Inhibition of the Wnt/β-catenin pathway enhances antitumor immunity in ovarian cancer Ther Adv Med Oncol 12 2020 1758835920913798
131 Wall J.A. Meza-Perez S. Scalise C.B. Manipulating the Wnt/β-catenin signaling pathway to promote anti-tumor immune infiltration into the TME to sensitize ovarian cancer to ICB therapy Gynecol Oncol 160 1 2021 285 294 33168307
132 Dholakia J. Scalise C.B. Katre A.A. Sequential modulation of the Wnt/β-catenin signaling pathway enhances tumor-intrinsic MHC I expression and tumor clearance Gynecol Oncol 164 1 2022 170 180 34844776
133 Ryland G.L. Hunter S.M. Doyle M.A. RNF43 is a tumour suppressor gene mutated in mucinous tumours of the ovary J Pathol 229 3 2013 469 476 23096461
134 Li Z. Wang Y. Li Y. Ube2s stabilizes β-Catenin through K11-linked polyubiquitination to promote mesendoderm specification and colorectal cancer development Cell Death Dis 9 5 2018 456 29674637
135 Hu W. Li M. Chen Y. Gu X. UBE2S promotes the progression and Olaparib resistance of ovarian cancer through Wnt/β-catenin signaling pathway J Ovarian Res 14 1 2021 121 34535173
136 Liu D. Song Z. Wang X. Ouyang L. Ubiquitin C-terminal hydrolase L5 (UCHL5) accelerates the growth of endometrial cancer via activating the Wnt/β-catenin signaling pathway Front Oncol 10 2020 865 32596150
137 Hu J. Meng Y. Yu T. Hu L. Mao M. Ubiquitin E3 ligase MARCH7 promotes ovarian tumor growth Oncotarget 6 14 2015 12174 12187 25895127
138 Meng Y. Hu J. Chen Y. Yu T. Hu L. Silencing MARCH1 suppresses proliferation, migration and invasion of ovarian cancer SKOV3 cells via downregulation of NF-κB and Wnt/β-catenin pathways Oncol Rep 36 5 2016 2463 2470 27633480
139 Li D. Zhang Z. TRIM37 promotes the aggressiveness of ovarian cancer cells and increases c-Myc expression by binding to HUWE1 Arch Biochem Biophys 728 2022 109372
140 Pan S. Chen R. Pathological implication of protein post-translational modifications in cancer Mol Aspect Med 86 2022 101097
141 Cruz Walma D.A. Chen Z. Bullock A.N. Yamada K.M. Ubiquitin ligases: guardians of mammalian development Nat Rev Mol Cell Biol 23 5 2022 350 367 35079164
142 Aliabadi F. Sohrabi B. Mostafavi E. Pazoki-Toroudi H. Webster T.J. Ubiquitin-proteasome system and the role of its inhibitors in cancer therapy Open Biol 11 4 2021 200390
143 Lange S.M. Armstrong L.A. Kulathu Y. Deubiquitinases: from mechanisms to their inhibition by small molecules Mol Cell 82 1 2022 15 29 34813758
144 Pan W. Luo Q. Yan X. A novel SMAC mimetic APG-1387 exhibits dual antitumor effect on HBV-positive hepatocellular carcinoma with high expression of cIAP2 by inducing apoptosis and enhancing innate anti-tumor immunity Biochem Pharmacol 154 2018 127 135 29679556
145 Chen D.S. Mellman I. Elements of cancer immunity and the cancer-immune set point Nature 541 7637 2017 321 330 28102259
146 Sharma P. Hu-Lieskovan S. Wargo J.A. Ribas A. Primary, adaptive, and acquired resistance to cancer immunotherapy Cell 168 4 2017 707 723 28187290
147 Fu C. Zhu X. Xu P. Li Y. Pharmacological inhibition of USP7 promotes antitumor immunity and contributes to colon cancer therapy OncoTargets Ther 12 2019 609 617
148 Fang D.D. Tang Q. Kong Y. MDM2 inhibitor APG-115 synergizes with PD-1 blockade through enhancing antitumor immunity in the tumor microenvironment J Immunother Cancer 7 1 2019 327 31779710
149 Nachmias B. Ashhab Y. Ben-Yehuda D. The inhibitor of apoptosis protein family (IAPs): an emerging therapeutic target in cancer Semin Cancer Biol 14 4 2004 231 243 15219616
150 Huang Hk Joazeiro C.A. Bonfoco E. Kamada S. Leverson J.D. Hunter T. The inhibitor of apoptosis, cIAP2, functions as a ubiquitin-protein ligase and promotes in vitro monoubiquitination of caspases 3 and 7 J Biol Chem 275 35 2000 26661 26664 10862606
151 Fulda S. Molecular pathways: targeting inhibitor of apoptosis proteins in cancer: from molecular mechanism to therapeutic application Clin Cancer Res 20 2 2014 289 295 24270683
152 Infante J.R. Dees E.C. Olszanski A.J. Phase I dose-escalation study of LCL161, an oral inhibitor of apoptosis proteins inhibitor, in patients with advanced solid tumors J Clin Oncol 32 28 2014 3103 3110 25113756
153 DiPersio J.F. Erba H.P. Larson R.A. Oral Debio1143 (AT406), an antagonist of inhibitor of apoptosis proteins, combined with daunorubicin and cytarabine in patients with poor-risk acute myeloid leukemia — results of a phase I dose-escalation study Clin Lymphoma, Myeloma & Leukemia 15 7 2015 443 449
154 Noonan A.M. Bunch K.P. Chen J.Q. Pharmacodynamic markers and clinical results from the phase 2 study of the SMAC mimetic birinapant in women with relapsed platinum-resistant or -refractory epithelial ovarian cancer Cancer 122 4 2016 588 597 26566079
155 Xiao R. Allen C.T. Tran L. Antagonist of cIAP1/2 and XIAP enhances anti-tumor immunity when combined with radiation and PD-1 blockade in a syngeneic model of head and neck cancer OncoImmunology 7 9 2018 e1471440
156 Kearney C.J. Lalaoui N. Freeman A.J. Ramsbottom K.M. Silke J. Oliaro J. PD-L1 and IAPs co-operate to protect tumors from cytotoxic lymphocyte-derived TNF Cell Death Differ 24 10 2017 1705 1716 28665401
157 Chesi M. Mirza N.N. Garbitt V.M. IAP antagonists induce anti-tumor immunity in multiple myeloma Nat Med 22 12 2016 1411 1420 27841872
158 Beug S.T. Beauregard C.E. Healy C. Smac mimetics synergize with immune checkpoint inhibitors to promote tumour immunity against glioblastoma [published correction appears in Nat Commun. 2018 Jul 18;9:16231] Nat Commun 8 2017 14278
159 Momand J. Zambetti G.P. Olson D.C. George D. Levine A.J. The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation Cell 69 7 1992 1237 1245 1535557
160 Wang H.Q. Mulford I.J. Sharp F. Inhibition of MDM2 promotes antitumor responses in p53 wild-type cancer cells through their interaction with the immune and stromal microenvironment Cancer Res 81 11 2021 3079 3091 33504557
161 Wang L. Kumar S. Dahiya S. Ubiquitin-specific protease-7 inhibition impairs Tip60-dependent Foxp3 + T-regulatory cell function and promotes antitumor immunity EBioMedicine 13 2016 99 112 27769803
162 Amaravadi Ravi K. Schilder Russell J. Martin Lainie P. A phase I study of the SMAC-mimetic birinapant in adults with refractory solid tumors or lymphoma Mol Cancer Therapeut 14 11 2015 2569 2575
163 Igarashi Y. Sasada T. Cancer vaccines: toward the next breakthrough in cancer immunotherapy J Immunol Res 2020 2020 5825401
164 Soumia M. Hajji H. El Mzibri M. In-silico molecular modeling studies to identify novel potential inhibitors of HPV E6 protein Vaccines 10 9 2022 1452 36146532
165 Zou W. Immunosuppressive networks in the tumour environment and their therapeutic relevance Nat Rev Cancer 5 4 2005 263 274 15776005
166 Dougan M. Dougan S. Slisz J. IAP inhibitors enhance co-stimulation to promote tumor immunity J Exp Med 207 10 2010 2195 2206 20837698
167 Goodwin J.G. Chunduru S. Kamat A.M. Smac mimetic enables the anticancer action of BCG-stimulated neutrophils through TNF-α but not through TRAIL and FasL J Leukoc Biol 92 1 2012 233 244 22517918
168 Pan K. Farrukh H. Chittepu V.C.S.R. Xu H. Pan C.X. Zhu Z. CAR race to cancer immunotherapy: from CAR T, CAR NK to CAR macrophage therapy J Exp Clin Cancer Res 41 1 2022 119 35361234
169 Michie J. Beavis P.A. Freeman A.J. Antagonism of IAPs enhances CAR T-cell efficacy Cancer Immunol Res 7 2 2019 183 192 30651288
170 Boyerinas B. Jochems C. Fantini M. Antibody-dependent cellular cytotoxicity activity of a novel anti-PD-L1 antibody avelumab (MSB0010718C) on human tumor cells Cancer Immunol Res 3 10 2015 1148 1157 26014098
171 Glassman P.M. Balthasar J.P. Mechanistic considerations for the use of monoclonal antibodies for cancer therapy Cancer Biol Med 11 1 2014 20 33 24738036
172 Kimiz-Gebologlu I. Gulce-Iz S. Biray-Avci C. Monoclonal antibodies in cancer immunotherapy Mol Biol Rep 45 6 2018 2935 2940 30311129
173 Sathyanarayanan V. Neelapu S.S. Cancer immunotherapy: strategies for personalization and combinatorial approaches Mol Oncol 9 10 2015 2043 2053 26548534
174 Zhang M. Wen B. Anton O.M. IL-15 enhanced antibody-dependent cellular cytotoxicity mediated by NK cells and macrophages Proc Natl Acad Sci U S A 115 46 2018 E10915-E10924
175 Hideshima T. Ogiya D. Liu J. Immunomodulatory drugs activate NK cells via both Zap-70 and cereblon-dependent pathways Leukemia 35 1 2021 177 188 32238854
176 Wei W. Lin Y. Song Z. A20 and RBX1 regulate brentuximab vedotin sensitivity in Hodgkin lymphoma models Clin Cancer Res 26 15 2020 4093 4106 32299816
177 Sun W. Wang X. Wang D. CD40 × HER2 bispecific antibody overcomes the CCL2-induced trastuzumab resistance in HER2-positive gastric cancer J Immunother Cancer 10 7 2022 e005063
178 Wertz I.E. O'Rourke K.M. Zhou H. De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling Nature 430 7000 2004 694 699 15258597
179 Li X.Y. Wu J.C. Liu P. Inhibition of USP1 reverses the chemotherapy resistance through destabilization of MAX in the relapsed/refractory B-cell lymphoma Leukemia 37 1 2023 164 177 36352191
180 Wang G. Zhuang Z. Shen S. Regulation of PTEN and ovarian cancer progression by an E3 ubiquitin ligase RBCK1 Hum Cell 35 3 2022 896 908 35174471
181 Yagi H. Onoyama I. Asanoma K. Gα13-mediated LATS1 down-regulation contributes to epithelial-mesenchymal transition in ovarian cancer Faseb J 33 12 2019 13683 13694 31569999
182 Liu W. Zhan Z. Zhang M. KAT6A, a novel regulator of β-catenin, promotes tumorigenicity and chemoresistance in ovarian cancer by acetylating COP1 Theranostics 11 13 2021 6278 6292 33995658
183 Saleh M.N. Patel M.R. Bauer T.M. Phase 1 trial of ALRN-6924, a dual inhibitor of MDMX and MDM2, in patients with solid tumors and lymphomas bearing wild-type TP53 Clin Cancer Res 27 19 2021 5236 5247 34301750
184 Zhou X. Sun S.C. Targeting ubiquitin signaling for cancer immunotherapy Signal Transduct Targeted Ther 6 1 2021 16
