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Deubiquitinases in lung cancer: Oncogenic mechanisms, metabolic reprogramming, immune evasion, and therapeutic
Yi Wang1, Shujing Shi1, Jun Guo2
1Department of Pulmonary and Critical Care Medicine, Beijing Haidian Hospital, Beijing 100080, China.
Abstract:
Lung cancer, encompassing lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LSCC), and small cell lung cancer (SCLC), remains the leading cause of cancer-related mortality worldwide, with adaptive resistance to targeted therapies and immune checkpoint blockade limiting durable responses. Deubiquitinases (DUBs), proteases that remove ubiquitin marks and antagonize proteasomal degradation, are increasingly recognized as context-dependent regulators of oncogenic protein stability, metabolic adaptation, immune evasion, and therapy resistance in lung cancer. Here, we synthesize preclinical evidence on a human DUB family within a subtype-aware framework. In KRAS-mutant non-small cell lung cancer (NSCLC), USP7, USP25, and OTUB1 sustain mutant KRAS abundance and MAPK output through complementary catalytic and scaffold mechanisms, whereas USP13 drives β-catenin-dependent epithelial-mesenchymal transition. In LSCC, USP28 stabilizes c-MYC, ΔNp63, and SREBP2; in LUAD, USP22 emerges as an integrative node coupling proliferation, EZH2-mediated MHC-I silencing, PD-L1 stabilization, and ferroptosis resistance; and in SCLC, USP1 mediates NK-cell evasion and MAST1-dependent cisplatin resistance, whereas USP13 sustains FASN-dependent cancer stem cell states. Multiple DUBs converge on glycolysis, ferroptosis defense, tumor-associated macrophage polarization, PD-L1/B7-H4 stability, and chemo-, targeted-, and radio-resistance programs. Therapeutic strategies are evolving from small-molecule inhibitors (GNE-6776, AZ1, and SJB2-043) to OTUB1-recruiting deubiquitinase-targeting chimeras (DUBTACs), DCAF-based PROTACs, and repurposed agents (rolapitant, ixazomib, and chidamide). Most evidence remains preclinical; substrate redundancy, validated biomarkers, and selectivity challenges must be addressed before DUB-directed strategies can be translated into biomarker-stratified combination therapies.
Insights
Deubiquitinases (DUBs) are key regulators of lung cancer progression and therapy resistance. Targeting DUBs shows promise for new lung cancer treatments, but challenges remain for clinical translation.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Lung cancer remains a leading cause of cancer mortality globally.
- Resistance to targeted therapies and immunotherapy limits durable responses in lung cancer patients.
- Deubiquitinases (DUBs) are emerging as critical regulators of cancer cell biology and therapeutic resistance.
Purpose of the Study:
- To synthesize preclinical evidence on the role of human DUBs in different lung cancer subtypes.
- To provide a subtype-aware framework for understanding DUB functions in lung cancer.
- To explore emerging therapeutic strategies targeting DUBs for lung cancer treatment.
Main Methods:
- Review and synthesis of preclinical evidence on human DUB family members in lung cancer.
- Analysis of DUB roles in specific lung cancer subtypes (NSCLC, LSCC, LUAD, SCLC).
- Examination of DUB involvement in oncogenic protein stability, metabolism, immune evasion, and therapy resistance.
Main Results:
- Specific DUBs (USP7, USP25, OTUB1, USP13, USP28, USP22, USP1) are implicated in driving key oncogenic pathways and resistance mechanisms across lung cancer subtypes.
- DUBs converge on critical processes including glycolysis, ferroptosis defense, immune evasion (PD-L1, B7-H4), and resistance to various therapies.
- Preclinical studies highlight diverse therapeutic strategies including small-molecule inhibitors, DUBTACs, PROTACs, and repurposed agents.
Conclusions:
- DUBs play multifaceted, context-dependent roles in lung cancer pathogenesis and therapeutic resistance.
- Targeting DUBs represents a promising avenue for novel lung cancer therapies.
- Further research is needed to address substrate redundancy, identify biomarkers, and overcome selectivity challenges for clinical translation.
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