Cuproptosis, a recently found kind of programmed cell death, has been linked to tumor development, prognosis, and therapeutic response. The roles of cuproptosis-related genes (CRG) in the tumor microenvironment (TME) are, nevertheless, unknown. We evaluated alterations in CRG and assessed the related expression patterns in 1445 lung cancer (LC) samples from three separate datasets, analyzing genetic, and transcriptional domains. We discovered two separate molecular subtypes of CRG and discovered that various subtypes of CRG were connected with patient clinical features and prognosis. Furthermore, we discovered connections between distinct CRG subtypes and TME cell infiltration features. The CRG_score was then developed and validated for predicting overall survival (OS). Following that, we investigated the relationship between CRG_score and the cancer stem cell (CSC) index and chemotherapeutic treatment sensitivity. In addition, we created a very accurate nomogram to increase the clinical usefulness of CRG_score. The potential roles of CRG in the tumor-immune-microenvironment, clinical characteristics, and prognosis in LC are demonstrated by our multiplex study. These findings expand our understanding of CRG in LC and may open up new options for assessing LC patients' prognosis and generating more effective immunotherapeutic treatments.
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