Aug 2026· Experimental Cell Research· pp.
115154
· 0 citations· 165 references
Medicine
TL;DR
The molecular mechanisms by which the UPS contributes to targeted therapy resistance in NSCLC are summarized, recent progress in emerging UPS-targeting strategies are evaluated, and the major barriers impeding their clinical translation are critically discussed.
Abstract
The introduction of tyrosine kinase inhibitors (TKIs) targeting driver oncogenes such as EGFR, ALK, and KRAS has substantially reshaped the treatment landscape of non-small cell lung cancer (NSCLC) and improved patient outcomes. However, inevitable acquired resistance remains the core obstacle to therapeutic success. Unlike previous studies that have largely focused on secondary mutations or bypass activation, the role of proteostasis imbalance in the evolution of resistance is increasingly recognized. The ubiquitin-proteasome system (UPS), as the central machinery for intracellular protein degradation and quality control, precisely regulates the stability, localization, and function of numerous key proteins, and is extensively involved in cell cycle progression, apoptosis, DNA damage repair, and various signaling pathways. Accumulating evidence indicates that UPS dysregulation is a critical factor in the emergence and maintenance of resistance to targeted therapy in NSCLC. By altering the expression and activity of specific E3 ligases or deubiquitinating enzymes (DUBs), resistant cells can remodel their proteome to achieve aberrant stabilization of pro-survival proteins, degradation of pro-apoptotic factors, or activation of alternative survival pathways, thereby adapting to TKI pressure. In light of this, developing interventions targeting core components of the UPS-such as next-generation proteasome inhibitors, molecular glues, PROTACs, and inhibitors of E3 ligases or DUBs-has emerged as a highly promising direction to overcome resistance. This review aims to systematically summarize the molecular mechanisms by which the UPS contributes to targeted therapy resistance in NSCLC, evaluate recent progress in emerging UPS-targeting strategies-most of which remain at preclinical or early clinical stages-and critically discuss the major barriers impeding their clinical translation, including off-target toxicity, selectivity issues, and the need for rationally designed combination regimens.
Therapy resistance in gastrointestinal tumors remains a critical challenge in clinical oncology, severely compromising therapeutic efficacy and long-term patient survival. E3 ubiquitin ligases, as core enzymes involved in the protein ubiquitination process, have been demonstrated to play indispensable roles in regulating key biological processes in tumor cells, including DNA damage repair, cell cycle progression, apoptosis, cancer stem cell maintenance, and immune evasion. Additionally, E3 ligases are key regulators of resistance to multiple anticancer strategies, such as chemotherapy, radiotherapy, targeted therapy, and immunotherapy. This review systematically summarizes the functions and mechanisms of E3 ligases in DNA damage response and cancer therapy resistance, and further highlight recent advances in therapeutic approaches by targeting specific E3 ligases. Notably, combining E3 inhibitors with existing anticancer therapies may substantially enhance treatment responses and improve patient prognosis, providing a solid theoretical basis for future clinical applications.
Teng Ma, Yong-Zhu Zhou, Xiao-Jun Li et al.· Frontiers in Oncology· 0 citations
Emerging evidence has expanded the functional repertoire of SKP2 beyond cell cycle control to encompass metabolism, DNA repair, stemness, tumor microenvironment and immunotherapy response, positioning it as an increasingly attractive target for intervention.
Sheng-An Zheng, Cheng Wang, Xiao-Die Yao et al.· Drug Design, Development and...· 0 citations
A review of the molecular characteristics and physiological functions of USP28, its context-dependent roles in neoplastic diseases, and its translational implications for targeted therapy and biomarker discovery highlights its potential as a therapeutic target for precision medicine.
Tongyong Luo, Shuncai Wu, Qing-Song Wang et al.· Frontiers in Immunology· 1 citation
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by poor clinical outcomes. Owing to the absence of estrogen receptors, progesterone receptors, and Human Epidermal Growth Factor Receptor 2 (HER2) expression, TNBC shows limited responsiveness to conventional endocrine and targeted therapies. This subtype exhibits strong heterogeneity, a high propensity for metastasis, and a tendency to develop acquired drug resistance. Its survival and progression largely rely on non-classical signaling pathways, including Epidermal growth factor receptor (EGFR), Phosphoinositide 3-kinase/Protein Kinase B (PI3K/AKT), and Notch, which collectively impose substantial challenges to clinical management. In recent years, protein post-translational modifications—particularly ubiquitination and ubiquitin-like modifications—have emerged as key mechanisms governing TNBC malignant progression. This review systematically summarizes the stage-specific regulatory roles of ubiquitination during TNBC initiation, progression, and therapeutic resistance. These mechanisms include modulation of tumor stemness, epithelial–mesenchymal transition, DNA damage repair, ferroptosis, and immune evasion through the regulation of critical proteins such as Toll-like receptor 4/Nuclear factor kappa-B (TLR4/NF-κB), Twist family bHLH transcription factor 1 (TWIST1), Poly (ADP-Ribose) Polymerase 1 (PARP1), Programmed death-ligand 1 (PD-L1), and Glutathione Peroxidase 4 (GPX4). In addition, ubiquitin-like modifications (including small ubiquitin-like modifier (SUMOylation), Neural precursor cell expressed developmentally downregulated protein 8 (NEDDylation), and Interferon-stimulated gene (ISGylation)) function synergistically in maintaining genome stability, transcriptional regulation, and immunological processes. Furthermore, this review highlights the translational potential of targeting ubiquitination pathways in TNBC, covering the applications, advantages, and limitations of immune checkpoint inhibitors, Poly ADP-ribose polymerase (PARP) inhibitors, antibody–drug conjugates, and combination treatment strategies. Finally, it outlines future research directions, such as developing a TNBC-specific ubiquitinome landscape, creating highly selective E3 ligase or deubiquitinase inhibitors, and integrating multi-omics with artificial intelligence technologies. These advances are expected to provide a theoretical foundation and translational insights for precision interventions targeting protein homeostasis in TNBC.
Yongpan Wang, Wei-Qiang Huang, Qizhuan Lin et al.· Oncology Research· 0 citations
The combination of radiation therapy and immunotherapy has become a cornerstone of modern clinical cancer treatment. However, the inherent radiation resistance of tumors and complex immune evasion mechanisms remain major bottlenecks limiting their long-term effects and sustained efficacy. E3 ubiquitin ligases critically influence tumor sensitivity to radioimmunotherapy by controlling protein stability across DNA repair, immune signaling, and stress-response pathways. This review systematically dissects the multidimensional molecular network through which E3 ubiquitin ligases regulate radiosensitivity and immunoresponsiveness. At the intracellular level, we provide an in-depth analysis of how E3 ubiquitin ligases determine the fate of radiation-induced damage repair by precisely regulating the kinetics of the DNA damage response (DDR), cell cycle checkpoints, and apoptosis thresholds. At the extracellular level, this study focuses on the key roles of E3 ubiquitin ligases in reshaping the immune microenvironment, including the maintenance of spatiotemporal stability of immune checkpoints, the fidelity of antigen processing and presentation, and the epigenetic regulation of microenvironmental dynamic plasticity. Recent studies indicate that E3 ubiquitin ligases link radiation-induced DDR signaling to innate and adaptive immune activation, particularly through the induction of immunogenic cell death (ICD) and the calibration of innate immune sensing pathways like cGAS-STING. Finally, we provide a comprehensive synthesis of cutting-edge translational strategies targeting E3 ubiquitin ligases—ranging from canonical inhibitors to transformative proteolysis-targeting chimeras (PROTACs) and molecular glue degraders (MGDs)—offering novel paradigms for overcoming therapeutic resistance and refining personalized radioimmunotherapy.
Qian Yang, Xin-Ruo Xing, Yi-Chang Wang et al.· Molecular Cancer· 0 citations
The ubiquitin-proteasome system is a master regulator of anti-tumor immunity in lung cancer, which primarily functions through controlling the stability of immune checkpoint proteins. The present review offers a synthesis concerning how a dynamic balance between E3 ubiquitin ligases (E3s) and deubiquitinases (DUBs) dictates the fate of key checkpoint proteins, including programmed cell death protein 1/programmed death-ligand 1, lymphocyte-activating gene 3 and B7 homolog 4. Although specific E3s are known to promote checkpoint degradation to enhance T-cell function in certain contexts, and DUBs frequently stabilize these proteins to foster immune evasion, these effects are context-dependent; for example, certain E3s are paradoxically able to promote immune evasion, whereas the inhibition of select DUBs synergizes with immune checkpoint blockade. This regulatory interplay extends to core oncogenic pathways, including the phosphoinositide 3-kinase/AKT and mitogen-activated protein kinase signaling pathways, which indirectly modulate checkpoint expression. Therapeutically, targeting these enzymes with various agents, such as the ubiquitin-specific peptidase 7 inhibitor P5091 or the repurposed drug canagliflozin, has the effect of synergizing with immune checkpoint blockade through reshaping the tumor microenvironment. However, clinical translation is challenged by tumor heterogeneity, pathway redundancy and the complexity of the ubiquitin network. Future progress in this area hinges on precision drug design, predictive biomarker development and rational combination therapies that are informed by a deeper mechanistic understanding of ubiquitin-driven immune regulation.
Lin Chai, Linrong Pang, Yi-Ting Li et al.· Experimental and Therapeutic...· 0 citations
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