Integrated Multi‐Omics Profiling to Characterize Molecular Subtypes and Reveal Potential Therapeutic Strategies for Colorectal Cancer

Colorectal cancer (CRC) is a complex and heterogeneous disease with limited effective treatment options. To investigate the molecular features and potential therapeutic strategies for CRC patients, including both early‐onset colorectal cancer (EOCRC) and late‐onset colorectal cancer (LOCRC) cases, a comprehensive multi‐omics approach was employed. Whole exome sequencing (WES), RNA sequencing (RNA‐seq), and proteomic and phosphoproteomic profiling were performed on paired tumor and normal adjacent tissue (NAT) from 144 CRC patients, totaling 672 samples. Three distinct molecular subtypes were identified, each exhibiting unique clinical prognoses and molecular characteristics. The S_I subtype was associated with the worst prognosis and a greater prevalence of EOCRC. Moreover, it exhibited a higher stromal score, characterized by increased infiltration of fibroblasts, mesenchymal stem cells, and adipocytes, when compared with the S_II and S_III subtypes. Additionally, the S_II subtype showed a higher immune score. Drug testing using cell lines and patient‐derived three‐dimensional (3D) bioprinted models revealed that S_I tumors were more responsive to Alisertib, suggesting subtype‐specific therapeutic potential. Our study characterized the multi‐omics landscape of CRC, offering critical insights into its molecular heterogeneity. These findings enhance our understanding of the molecular mechanisms underlying CRC and contribute to the development of personalized treatment strategies.