Multi-Omics Analysis Reveals m7G Methylation-Related Genes May Be Involved in TGF-β Signaling-Mediated Anti-PD-L1...

Area of Science:

• Oncology
• Molecular Biology
• Immunotherapy

Background:

• Immunotherapy resistance is a major hurdle in bladder cancer treatment.
• The role of N7-methylguanosine (m7G) methylation in bladder cancer immunotherapy resistance is not well understood.
• This study investigates m7G methylation-related genes (m7GRGs) in bladder cancer immunotherapy resistance.

Purpose of the Study:

• To explore the role of m7G methylation-related genes (m7GRGs) in bladder cancer immunotherapy resistance.
• To identify molecular subtypes of bladder cancer based on m7GRGs.
• To investigate the association between m7GRGs, tumor microenvironment, and response to anti-PD-L1 therapy.

Main Methods:

• Multi-omics data integration (bulk, single-cell, spatial transcriptomics) from public bladder cancer cohorts.
• Machine learning for molecular clustering and signature gene identification.
• In vitro validation including gene knockdown, qRT-PCR, Western blot, IHC, CCK-8, and wound healing assays.

Main Results:

• Two distinct molecular clusters were identified, with C1 showing poorer prognosis, higher m7GRGs expression, and an immunosuppressive microenvironment.
• NUDT10 was identified as a key prognostic gene linked to molecular clusters and associated with anti-PD-L1 resistance.
• NUDT10 co-expression with TGF-β activator LRRC32 was observed, and their expression correlated with poor response to anti-PD-L1 therapy.

Conclusions:

• NUDT10 is a key gene associated with poor prognosis in m7GRGs-defined bladder cancer clusters.
• NUDT10 may regulate TGF-β signaling and is linked to resistance to anti-PD-L1 therapy in advanced bladder cancer.
• Targeting NUDT10 could be a potential strategy for overcoming immunotherapy resistance in bladder cancer.