Deubiquitinases in lung cancer: Oncogenic mechanisms, metabolic reprogramming, immune evasion, and therapeutic targeting.
Source: PubMed, NCBI / U.S. National Library of Medicine
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 s
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.