Non-small cell lung cancer (NSCLC) represents a heterogeneous group of malignancies characterised by diverse histological and molecular features. Some NSCLCs, particularly adenocarcinomas, harbour genomic alterations in receptor tyrosine kinases or downstream RAS/RAF signalling pathways, which are targets of effective therapies. NSCLCs lacking actionable genomic alterations often benefit from immune checkpoint inhibitors, though only a minority of patients achieve long-term survival. These tumours often carry alterations in tumour suppressor genes like TP53, KEAP1, STK11, or NF1, for which pharmacological strategies are still under investigation. This review explores emerging therapeutic opportunities unveiled by multi-omics studies in NSCLCs without actionable genomic alterations. Proteogenomic approaches-integrating genomic, transcriptomic and proteomic data-enable a comprehensive understanding of NSCLC molecular landscapes and signalling network dysregulation, helping to identify distinct tumour subtypes and potential therapeutic targets. These tumours exhibit alterations in cell cycle regulation, DNA repair, immune signalling, epigenetic modulation and metabolic and redox pathways. Although therapies targeting tumour suppressor genes like p53 remain highly anticipated, extending our understanding of the broader molecular landscape in these tumours may reveal novel vulnerabilities and inform the development of novel drugs or combination strategies. This could further advance precision oncology for NSCLC.
