Multiomics Analysis Reveals Cuproptosis-Related Signature for Evaluating Prognosis and Immunotherapy Efficacy in Colorectal Cancer

SIMPLE SUMMARY: Cuproptosis is a newly discovered copper-dependent cell death. We aimed to explore the functions of cuproptosis in the tumor microenvironment and construct a cuproptosis-related prognosis signature for survival prediction and immunotherapeutic strategies. We comprehensively analyzed single-cell RNA-seq and bulk RNA-seq data from multiple colorectal cancer cohorts based on TCGA and GEO databases in the current study. The relationship between molecular clusters, clinical outcomes, and immune cell infiltration characteristics associated with cuproptosis was investigated. Considering the heterogeneity of colorectal cancer development, we then established a validated five-gene panel for predicting individual patient prognosis, drug sensitivity, tumor-immune microenvironment, and immunotherapy targets. ABSTRACT: Cuproptosis is a copper-induced form of mitochondrial cell death which is engaged in the proliferation and migration of a variety of tumors. Nevertheless, the role of cuproptosis in tumor microenvironment (TME) remodeling and antitumor therapy is still poorly understood. We characterized two diverse cuproptosis-associated molecular isoforms in CRC which exhibit distinct prognostic and TME characteristics. Subsequently, we constructed a cuproptosis-associated prognostic model containing five genes and divided the patients into a high CPS-score group and a low CPS-score group. Univariate and multivariate Cox analyses showed that the CPS score could be used as an independent prognostic factor. The nomogram, and its consequent calibration curves, indicated that this prognostic signature had good predictive power for CRC. The analysis of single-cell sequencing data showed the significant expression of HES4 and SPHK1 in various immune and stromal (including fibroblasts) cells. Further studies showed that tumor mutational burden (TMB), high microsatellite instability (MSI-H) ratio, immune checkpoint blockade (ICB), and human leukocyte antigen (HLA) gene expression all positively correlated with the CPS score, predicting a better reaction to immunotherapy in high CPS-core patients. The CPS score constructed from cuproptosis subtypes can be used as a predictive tool to evaluate the prognosis of CRC patients and their response to immunotherapy.