Identification of cuproptosis-related subtypes in lung adenocarcinoma and its potential significance.

Cuproptosis is a novel and unique cell death mode that has attracted significant interest in recent years. Little is currently known about whether cuproptosis-related genes (CRGs) are associated with the pathophysiology and survival of patients with lung adenocarcinoma (LUAD). The present study sought to characterize the transcriptional and genetic alteration of CRGs in LUAD and its potential significance in the tumor microenvironment and predicting the prognosis of LUAD. The secondary eventual aim was to study the role of CRGs in predicting immunotherapy response and its clinical value combined with the TNM stage. We found that several CRGs, including FDX1, DLD, SLC31A1, and MTF1, were enriched in macrophages in our single-cell RNA-seq data. Three distinct molecular subtypes were identified and correlated with clinicopathological characteristics, prognosis, biological pathways, and tumor microenvironment (TME) in LUAD. We developed a cuproptosis-related gene score (CRG_score) and validated it in three independent cohorts and clinical subtypes. The low CRG_score group, characterized by a greater immune score, immunophenoscore (IPS), lower tumor immune dysfunction and exclusion (TIDE) score, and T-cell dysfunction score, had a better prognosis, suggesting that the low CRG_score group responded more favorably to immunotherapy, which was validated in the anti-PD-1/L1 immunotherapy cohort (IMvigor210). In contrast, the high CRG_score group was more sensitive to targeted therapy and chemotherapy, with a higher cancer stem cell (CSC) index and lower half-maximal inhibitory concentration (IC50) for many drugs. Given the established crosstalk between CRG_score and tumor TNM stage, we developed an accurate nomogram for clinical application of the CRG_score. Taken together, our rigorous and comprehensive examination of CRGs in LUAD identified their potential functions in TME, clinicopathological characteristics, drug sensitivity, and prognosis. These findings improve the current understanding of cuproptosis in LUAD, paving the way for more accurate prognosis assessment and tailored treatment for this patient population.