Molecular Subtypes Based on Cuproptosis-Related Genes and Tumor Microenvironment Infiltration Characterization in Colorectal Cancer.

Abstract

Recent studies have demonstrated the biological significance of cuproptosis modification, a newly discovered programmed cell death, in tumor progression. Nonetheless, the potential role of cuproptosis-related genes (CRGs) in the immune landscape and tumor microenvironment (TME) formation of colorectal cancer (CRC) remains unknown. We comprehensively assessed cuproptosis modification patterns of 1339 CRC samples based on 27 CRGs and systematically analyzed the correlation of these patterns with TME. The CRG-score was constructed to quantify cuproptosis characteristics by LASSO and multivariate Cox regression methods, and its predictive capability was validated in an independent cohort. We identified three distinct cuproptosis modification patterns in CRC. The TME immune cell infiltration demonstrated immune heterogeneity among these three subtypes. Enrichment for multiple metabolism signatures was pronounced in cluster A. Cluster C was significantly correlated with the signaling pathways of immune activation-related, resulting in poor prognoses. Cluster B with mixed features possibly represents a transition phenotype or intratumoral heterogeneity. Then, based on constructed eight-gene CRG-score, we found that the signature could predict the disease-free survival of CRC patients, and the low CRG-score was related to increased neoantigen load, immunity activation, and microsatellite instability-high (MSI-H). Additionally, we observed significant correlations of the CRG-score with the cancer stem cell index and chemotherapeutic drug susceptibility. This study demonstrated that cuproptosis was correlated with tumor progression, prognosis, and TME. Our findings may improve the understanding of CRGs in TME infiltration characterization of CRC patients and contribute to guiding more effective clinical therapeutic strategies.