Integrative multi‐omic and machine learning approach for prognostic stratification and therapeutic targeting in lung squamous cell carcinoma

The proliferation, metastasis, and drug resistance of cancer cells pose significant challenges to the treatment of lung squamous cell carcinoma (LUSC). However, there is a lack of optimal predictive models that can accurately forecast patient prognosis and guide the selection of targeted therapies. The extensive multi-omic data obtained from multi-level molecular biology provides a unique perspective for understanding the underlying biological characteristics of cancer, offering potential prognostic indicators and drug sensitivity biomarkers for LUSC patients. We integrated diverse datasets encompassing gene expression, DNA methylation, genomic mutations, and clinical data from LUSC patients to achieve consensus clustering using a suite of 10 multi-omics integration algorithms. Subsequently, we employed 10 commonly used machine learning algorithms, combining them into 101 unique configurations to design an optimal performing model. We then explored the characteristics of high- and low-risk LUSC patient groups in terms of the tumor microenvironment and response to immunotherapy, ultimately validating the functional roles of the model genes through in vitro experiments. Through the application of 10 clustering algorithms, we identified two prognostically relevant subtypes, with CS1 exhibiting a more favorable prognosis. We then constructed a subtype-specific machine learning model, LUSC multi-omics signature (LMS) based on seven key hub genes. Compared to previously published LUSC biomarkers, our LMS score demonstrated superior predictive performance. Patients with lower LMS scores had higher overall survival rates and better responses to immunotherapy. Notably, the high LMS group was more inclined toward "cold" tumors, characterized by immune suppression and exclusion, but drugs like dasatinib may represent promising therapeutic options for these patients. Notably, we also validated the model gene SERPINB13 through cell experiments, confirming its role as a potential oncogene influencing the progression of LUSC and as a promising therapeutic target. Our research provides new insights into refining the molecular classification of LUSC and further optimizing immunotherapy strategies.