Yi Zhang ^1* Yuzhi Wang ² Haitao Qian ^3*

• ¹ Guang'an People's Hospital, Guang'an, China
• ² People’s Hospital of Deyang City, Deyang, Sichuan Province, China
• ³ The First People’s Hospital of Lianyungang, Lianyungang, Jiangsu Province, China

Lung adenocarcinoma (LUAD) is a heterogeneous tumor characterized by diverse genetic and molecular alterations. Developing a multi-omics-based classification system for LUAD is urgently needed to advance biological understanding. Data on clinical and pathological characteristics, genetic alterations, DNA methylation patterns, and the expression of mRNA, lncRNA, and microRNA, along with somatic mutations in LUAD patients, were gathered from the TCGA and GEO datasets. A computational workflow was utilized to merge multi-omics data from LUAD patients through 10 clustering techniques, which were paired with 10 machine learning methods to pinpoint detailed molecular subgroups and refine a prognostic risk model. The disparities in somatic mutations, copy number alterations, and immune cell infiltration between highrisk and low-risk groups were assessed. The effectiveness of immunotherapy in patients was evaluated through the TIDE and SubMap algorithms, supplemented by data from various immunotherapy groups. Furthermore, the Cancer Therapeutics Response Portal (CTRP) and the PRISM Repurposing dataset (PRISM) were employed to investigate new drug treatment approaches for LUAD. In the end, the role of SLC2A1 in tumor dynamics was examined using RT-PCR, immunohistochemistry, CCK-8, wound healing, and transwell tests. By employing multi-omics clustering, we discovered two unique cancer subtypes linked to prognosis, with CS2 demonstrating a better outcome.A strong model made up of 17 genes was created using a random survival forest (RSF) method, which turned out to be an independent predictor of overall survival and showed reliable and impressive performance. The low-risk group not only had a better prognosis but was also more likely to display the "cold tumor" phenotype. On the other hand, individuals in the high-risk group showed a worse outlook and were more likely to respond positively to immunotherapy and six particular chemotherapy medications.Laboratory cell tests demonstrated that SLC2A1 is abundantly present in LUAD tissues and cells, greatly enhancing the proliferation and movement of LUAD cells. Thorough examination of multi-omics data offers vital understanding and improves the molecular categorization of LUAD. Utilizing a powerful machine learning system, we highlight the immense potential of the riskscore in providing individualized risk evaluations and customized treatment suggestions for LUAD patients.