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Review Open Access

Molecular mechanisms and potential targeting strategies of ubiquitin‑proteasome system‑mediated PD‑1/PD‑L1 ubiquitination in tumor immune suppression (Review)

  • Authors:
    • Li-Hui Gu
    • Ai Guo
    • Yi-Yue Ding
    • Xue-Jie Wang
    • Hong-Xing Zhang
    • Wan-Li Duan
    • Bao-Gang Zhang
  • View Affiliations / Copyright

    Affiliations: Department of Diagnostic Pathology, School of Basic Medical Sciences, Shandong Second Medical University, Weifang, Shandong 261053, P.R. China, Department of Diagnostic Pathology, Shaoxing People's Hospital, Shaoxing, Zhejiang 312000, P.R. China, Medical Research Center, Shaoxing People's Hospital, Shaoxing, Zhejiang 312000, P.R. China
    Copyright: © Gu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 167
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    Published online on: September 26, 2025
       https://doi.org/10.3892/or.2025.9000
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Abstract

Cancer cells play a pivotal role in immune evasion by activating the programmed cell death protein 1 (PD‑1)/PD‑ligand (L)1 signaling pathway or immune cells within the tumor microenvironment. The ubiquitin‑proteasome system (UPS), the primary pathway for intracellular protein degradation, has been increasingly implicated in mediating tumor immune escape and resistance to anti‑PD‑1/PD‑L1 therapy. Targeting the UPS has demonstrated significant potential in improving the efficacy of tumor immunotherapy. Therefore, a deeper understanding of the molecular mechanisms by which UPS contributes to tumor resistance against PD‑1/PD‑L1 blockade, along with the optimization of UPS‑targeted small‑molecule drug design, holds scientific and clinical significance. In the present review, the role of UPS in tumor immune evasion through the regulation of PD‑1/PD‑L1 ubiquitination was discussed and potential therapeutic agents that may enhance the effectiveness of anti‑PD‑1/PD‑L1 treatment are summarized. These insights provide a theoretical foundation for advancing cancer immunotherapy and developing novel combination strategies.
View Figures

Figure 1

Protein degradation mediated by the
UPS and tumor immune evasion mediated by PD-1/PD-L1. (A) The UPS
consists of three components: a ubiquitination modification system
mediated by a three-step enzymatic cascade, the proteasome; and the
deubiquitination process. (B) In the tumor microenvironment, the
heterodimer formed between the ITSM of PD-1 and SHP-2 inhibits TCR
signal activation, while the dimer formed by ITIM and SHP-1 further
enhances TCR suppression, thereby promoting tumor immune evasion.
UPS, ubiquitin-proteasome system; PD-1, programmed death receptor
1; PD-L1, programmed cell death ligand 1; ITSM, immunoreceptor
tyrosine-based activation motif; ITIM, immunoreceptor
tyrosine-based inhibitory motif; SHP-2, Src Homology 2
domain-containing Protein Tyrosine Phosphatase-2; TCR,
receptor-engineered; DUBs, deubiquitinating enzymes; SHP-1, Src
Homology 2 domain-containing Protein Tyrosine Phosphatase-1; 19S
RP, 19S regulatory particle; 20S CP, 20S core particle; MHC, major
histocompatibility complex.

Figure 2

The role of ubiquitination in the
treatment with anti-PD-1/PD-L1 mAb. The ubiquitination functions of
E3 ubiquitin ligases SPOP, TRIM21, ARIH1, MIB2, Skp2, NEDD4,
β-TrCP, ITCH and RNF125 can affect the immune capacity of tumors by
regulating the expression level of PD-L1. The ubiquitination
functions of E3 ubiquitin ligases FBXO38, KLHL22, FBW7 and c-Cbl
can influence the immune function of T cells by regulating the
expression level of PD-1. PD-1, programmed cell death protein 1;
PD-L1, programmed death-ligand 1; mAb, monoclonal antibodies; SPOP,
speckle-type POZ protein; TRIM21, tripartite motif-containing
protein 21; ARIH1, ariadne RBR E3 ubiquitin protein ligase 1; MIB2,
mind bomb E3 ubiquitin protein ligase 2; Skp2, S-phase
kinase-associated protein 2; NEDD4, neural precursor cell expressed
developmentally downregulated 4; β-Trcp, beta-transducin
repeat-containing protein; ITCH, itchy E3 ubiquitin protein ligase;
ITIM, immunoreceptor tyrosine-based inhibitory motif; RNF125, ring
finger protein 125; FBXO38, F-Box protein 38; KLHL22, kelch-like
protein 22; FBW7 F-Box and WD repeat domain-containing 7; c-Cbl,
Casitas b lymphoma; ALDH2, aldehyde dehydrogenase 2; BCLAF1
BCL2-associated transcription factor 1; β-Trcp beta-transducin
repeat-containing protein; CDH1 cadherin 1; CDK1 cyclin-dependent
kinase 1; CDK4 cyclin-dependent kinase 4; CDK5 cyclin-dependent
kinase 5; EGFR, epidermal growth factor receptor; FGFR3, fibroblast
growth factor receptor 3; GSK3α, glycogen synthase kinase 3 alpha;
GSK3β glycogen synthase kinase 3 beta; IL-2, interleukin-2; IL-18,
interleukin-18; LKB1, liver kinase B1; RAB8, RAS-related protein
Rab-8; SGLT2, sodium-glucose cotransporter 2; STAT5, signal
transducer and activator of transcription 5.

Figure 3

The role of deubiquitination in the
treatment with anti-PD-1/PD-L1 mAb. In cancer cells,
deubiquitinating enzymes such as CSN5, OTUB1, OTUB2, TRAF6, USP2,
USP7, USP8 and USP22 exert their deubiquitination functions to
regulate the expression level of PD-L1, thereby promoting tumor
immune evasion. In immune cells, the deubiquitinating enzyme USP5
exerts its deubiquitination function to regulate the expression
level of PD-1, thereby promoting tumor immune evasion. PD-1,
programmed death receptor 1; PD-L1, programmed cell death ligand 1;
mAb, monoclonal antibodies; CSN5, COP9 signalosome subunit 5;
OTUB1, OTU deubiquitinase, ubiquitin aldehyde binding 1; OTUB2, OTU
deubiquitinase, ubiquitin aldehyde binding 2; TRAF6, TNF
receptor-associated factor 6; USP2, ubiquitin-specific peptidase 2;
USP7, ubiquitin-specific peptidase 7; USP8, ubiquitin-specific
peptidase 8; USP22, ubiquitin-specific peptidase 22; USP5,
ubiquitin-specific peptidase 5; ANXA1, Annexin A1; ERK,
extracellular signal-regulated kinase; EZH2, enhancer of zeste
homolog 2; FXR1, fragile × mental retardation syndrome-related
protein 1; METTL3, methyltransferase-like 3; PKP3, plakophilin-3;
TNF-α, tumor necrosis factor-alpha; TNFR, TNF receptor; YTHDC1, YTH
domain-containing protein 1; K48, ubiquitin lysine 48-linked;

Figure 4

Potential drugs with the potential to
target the UPS for enhancing the efficacy of tumor immune
checkpoint inhibitors.
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Copy and paste a formatted citation
Spandidos Publications style
Gu L, Guo A, Ding Y, Wang X, Zhang H, Duan W and Zhang B: Molecular mechanisms and potential targeting strategies of ubiquitin‑proteasome system‑mediated PD‑1/PD‑L1 ubiquitination in tumor immune suppression (Review). Oncol Rep 54: 167, 2025.
APA
Gu, L., Guo, A., Ding, Y., Wang, X., Zhang, H., Duan, W., & Zhang, B. (2025). Molecular mechanisms and potential targeting strategies of ubiquitin‑proteasome system‑mediated PD‑1/PD‑L1 ubiquitination in tumor immune suppression (Review). Oncology Reports, 54, 167. https://doi.org/10.3892/or.2025.9000
MLA
Gu, L., Guo, A., Ding, Y., Wang, X., Zhang, H., Duan, W., Zhang, B."Molecular mechanisms and potential targeting strategies of ubiquitin‑proteasome system‑mediated PD‑1/PD‑L1 ubiquitination in tumor immune suppression (Review)". Oncology Reports 54.6 (2025): 167.
Chicago
Gu, L., Guo, A., Ding, Y., Wang, X., Zhang, H., Duan, W., Zhang, B."Molecular mechanisms and potential targeting strategies of ubiquitin‑proteasome system‑mediated PD‑1/PD‑L1 ubiquitination in tumor immune suppression (Review)". Oncology Reports 54, no. 6 (2025): 167. https://doi.org/10.3892/or.2025.9000
Copy and paste a formatted citation
x
Spandidos Publications style
Gu L, Guo A, Ding Y, Wang X, Zhang H, Duan W and Zhang B: Molecular mechanisms and potential targeting strategies of ubiquitin‑proteasome system‑mediated PD‑1/PD‑L1 ubiquitination in tumor immune suppression (Review). Oncol Rep 54: 167, 2025.
APA
Gu, L., Guo, A., Ding, Y., Wang, X., Zhang, H., Duan, W., & Zhang, B. (2025). Molecular mechanisms and potential targeting strategies of ubiquitin‑proteasome system‑mediated PD‑1/PD‑L1 ubiquitination in tumor immune suppression (Review). Oncology Reports, 54, 167. https://doi.org/10.3892/or.2025.9000
MLA
Gu, L., Guo, A., Ding, Y., Wang, X., Zhang, H., Duan, W., Zhang, B."Molecular mechanisms and potential targeting strategies of ubiquitin‑proteasome system‑mediated PD‑1/PD‑L1 ubiquitination in tumor immune suppression (Review)". Oncology Reports 54.6 (2025): 167.
Chicago
Gu, L., Guo, A., Ding, Y., Wang, X., Zhang, H., Duan, W., Zhang, B."Molecular mechanisms and potential targeting strategies of ubiquitin‑proteasome system‑mediated PD‑1/PD‑L1 ubiquitination in tumor immune suppression (Review)". Oncology Reports 54, no. 6 (2025): 167. https://doi.org/10.3892/or.2025.9000
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