Cervical cancer (CC) is the fourth worst gynecological malignancy (Bhatla et al., 2021; Volkova et al., 2021). Annually, 604,000 new instances of cervical cancer are diagnosed, with 342,000 deaths. Persistent infection with high-risk human papillomavirus (HR-HPV) is essential for the pathogenesis of CC (Bhatla and Singhal, 2020). Despite immunization and early detection by cytological screening has significantly reduced the incidence rate, CC is still a substantial healthcare issue, particularly in low-to middle-income nations (Tsikouras et al., 2016; Sung et al., 2021). Additionally, molecular mechanisms underlying CC still have not been fully clarified and because of resistance and recurrence, the long-term prognosis for CC remains dismal (Small et al., 2017; Bhatla and Singhal, 2020). Therefore, it is imperative to identify accurate and reliable risk models for the prognostic prediction and personalized treatment strategy of CC.

Recently, research on cuprotosis in tumors has increased rapidly. Cuprotosis is a novel mechanism of nonapoptotic cell death that is strongly linked to mitochondrial respiration (Wang et al., 2022; Zhao et al., 2022). Cuproptosis has been involved in the pathogenesis of multiple tumors, including hepatocellular carcinoma (Zhang et al., 2022), gastric cancer (Feng et al., 2022), colon adenocarcinoma (Xu et al., 2022a), etc. The accumulation of copper in the cell results in cell dysfunction and death (Tsvetkov et al., 2022). These findings prompt the role of cuproptosis in tumor pathology with a promising therapeutic target for refractory cancers. However, research on the impacts and processes of cuproptosis in CC is still in its initial stages.

Long noncoding RNAs (lncRNAs), with transcripts > 200 nucleotides, have gained extensive interest recently as a potentially essential element of biological regulation. Growing evidence reveals that lncRNAs are commonly dysregulated in cervical malignancies. LncRNA PTENP1 induces cell apoptosis and inhibits CC cell proliferation (Fan et al., 2020). LncRNA SNHG1 enhances cell proliferation, migration, and invasion in CC (Liu et al., 2018). LINC01305 promotes the progression of CC (Huang et al., 2021). Besides, several lncRNAs, including ferroptosis-related (Jiang et al., 2022), N6-methyladenosine (m6A)-related (Zhang et al., 2022), and immune-related (Zheng et al., 2020) lncRNA signatures, have recently been implicated in CC patients’ pathophysiology and prognosis. However, the impact of lncRNAs in mediating cuproptosis in CC has not been addressed.

Here, we identified a unique 6-cuproptosis-related lncRNA risk model in CC patients for predicting the prognosis and chemotherapy responsiveness while also characterizing the tumor immune microenvironment. In line with expectations, our model showed preferred effectiveness in terms of overall survival (OS), and immune cell infiltration in CC patients as well as immunological checkpoints, and medication sensitivity, which might provide new insights into the personalized treatment of CC patients.

Cervical cancer (CC) is a major public health issue in low and middle-income nations due to a lack of comprehensive screening programs (Tsikouras et al., 2016). Squamous cell carcinomas and adenocarcinomas are the most common histological kinds of CC, accounting for around 70% and 25% of all cervical malignancies, respectively (He et al., 2020; Park, 2020). HPV is the most prevalent but not the only risk factor for cervical cancer (He et al., 2020). Over 70% of HPV infections are caused by high-risk HPV, such as serotypes 16 and 18 (Small et al., 2017). It is challenging to access novel medicines for CC, in part due to immunological resistance. This necessitates the discovery of new biomarkers for monitoring CC development as well as therapeutic targets to increase survival rates.

Cuproptosis, a newly found kind of unique cell death, may reenergize research into the use of copper to treat cancer (Kahlson and Dixon, 2022). Copper is indispensable for sustained life activities since it is involved in mitochondrial respiration and iron absorption (Wang et al., 2022). However, it may be hazardous with the copper overloaded. There is currently little understanding of how copper regulates mortality in cancers. Copper ionophore treatment is more effective for cancers that express large levels of lipoylated tricarboxylic acid enzymes and undertake mitochondrial respiration (Tsvetkov et al., 2022). Despite the lack of clear evidence regarding the role of copper death-associated lncRNAs in CC, using copper toxicity may provide a promising therapeutic approach.

In CC pathology, lncRNAs appear to play a vital role in sustaining multiple biological activities. lncRNA abnormalities are linked to the onset and progression of CC (He et al., 2020). However, studies on cuproptosis-related lncRNAs that predict CC survival are scarce. Here, we sorted out 6 prognostic lncRNAs associated with cuproptosis-related genes (AJ003147.1, AC096992.2, SOX21-AS1, AL049869.2, CNNM3-DT, and ARHGAP31-AS1). SOX21-AS1, a multifunctional molecule involved in the immune- (Xu et al., 2022b), m7G- (Shao et al., 2022), and m6A-related (Xie et al., 2022) biological process in tumors, may impact CC etiology and prognosis. Li et al. demonstrated that SOX21-AS1 promotes cell proliferation, migration, and invasion in breast cancer (Li et al., 2021). The SOX21-AS1/miR-144-3p/PAK7 axis was shown to be carcinogenic in glioma cells through the Wnt/β-catenin pathway (Gai and Yuan, 2020) and SOX21-AS1 was found upregulated in lung cancer (Wang et al., 2021). In CC, SOX21-AS1 showed hypomethylation (Du et al., 2021) and could promote CC progression (Zhang et al., 2019). In addition, the heatmap of gene-lncRNA expression correlation (Figure 3C) indicates that lncRNA AJ003147.1 has a highly positive correlation with DLST. DLST is a glutamine regulator found in the tricarboxylic acid cycle (TCA) for oxidative decarboxylation. In individuals with neuroblastoma, a high DLST predicts poor treatment outcomes (Anderson et al., 2021). Suppression of the TCA cycle through DLST depletion decreases the invasion ability of triple-negative breast cancer (TNBC) (Shen et al., 2021). Targeting glutamine metabolism in immunosuppressive myeloid cells with DLST reduced their activity, resulting in a reduction in the immunosuppressive tumor microenvironment and therefore improving the effectiveness of immunotherapy in ovarian cancer (Udumula et al., 2021). LncRNAs are small RNAs precursors (Cheetham et al., 2013) and stimulate mRNA alternative splicing (Romero-Barrios et al., 2018). They affect protein transport and localization via post-translationally binding to targets (Huang and Zhang, 2014). In the present study, the selected lncRNAs all positively correlated with cuprotosis genes, indicating a potential regulatory function and cuproptosis targets for CC treatment. The remaining lncRNAs were demonstrated for the first time. Newly discovered knowledge of cuproptosis-related lncRNAs might help bring a breakthrough into clinical practice by improving the mechanistic understanding of CC.

We constructed a predictive risk model using 6 cuproptosis-related lncRNAs and our suggested model’s AUCs and C-index scores were higher than the other clinical features of CC patients, showing remarkable prediction potential. Furthermore, the risk score was substantially related to the clinical characteristics of CC. The risk model showed capability for independent prognostic prediction, and the survival curve findings demonstrate that the model is clinically applicable to CC patients.

For the treatment of CC, it offers great promise to combine immunogenic therapeutics with novel immunotherapeutic regimens (Attademo et al., 2020; Ferrall et al., 2021). The two risk groups exhibited distinct immunological microenvironments. Furthermore, high-risk individuals had increased activated Mast cells and decreased resting mast cells (Figure 7A) and showed a poorer activated Mast cells-related OS, as well as a better resting mast cells-related OS (Figures 7G,H), suggesting that the subgroup- or stated-related role of mast cells in TME. Generally, activated immune cells release proinflammatory cytokines and chemokines, which promote tumor cell growth (Ferrari et al., 2019). Mast cells release matrix metalloproteinases (MMPs) that aid tumor invasion and they actively stimulate neovascularization by producing conventional proangiogenic factors like VEGF, PDGF, and IL-6 (Komi and Redegeld, 2020). To further evaluate the practical applicability of immunotherapy, we assessed the TIDE score of the two groups. Observations of low-risk had lower TIDE scores, which suggests that, according to our risk model, low-risk patients would acquire more benefits from immunotherapy. Moreover, in line with the results of immune checkpoint detection, the low-risk group also showed a more robust checkpoint gene expression. Based on these findings, our signature might be a possible measure to evaluate the efficacy of immunotherapy in CC patients, and immune checkpoint inhibitor (ICI) medication may be a good option for low-risk patients. Aside from immunotherapy, we discovered chemotherapy prediction based on the risk model, and individuals of high risk were quite sensitive to the clinically applied therapy medications. These findings show that high-risk patients react better to chemotherapy and targeted medicines, which is significant for personalized cancer treatment. Overall, these discoveries might lead to new therapeutic options for CC sufferers and affect individualized tumor therapy.

Identifying various risk stratification groups’ signaling pathways may aid in a better understanding of the molecular biology process in CC. We observed that the DEGs of the two risk categories were associated with immune-related and metastatic processes utilizing the GO, KEGG, and DO analyses. GSEA showed DEGs enriched in the KEGG cytokine-cytokine pathway, which influences autoimmune, inflammatory, and viral disorders (Spangler et al., 2015). Our results suggested immune-related processes affected CC development, which was mediated by cuproptosis-related lncRNAs. This work offers a new foundation for future therapeutic methods by elucidating the involvement of cuproptosis-related lncRNAs in CC immune modulation.

The study’s key findings and implications were as follows. To begin, this work involves the first development and comprehensive investigation of a unique 6-cuproptosis-related lncRNA risk model to predict CC patients’ prognosis. Second, risk score in the model was found connected to clinicopathological characteristics, immune infiltration, and TIDE score change, which may shed light on tumor state prediction and antitumor response, potentially giving targets for future therapeutic intervention. Third, sensitive drug prediction might be a possible therapeutic technique for improving the effectiveness of CC immunotherapy, and providing tailored ramifications for personalized cuproptosis-related lncRNAs may predict prognosis and aid in the development of a viable treatment approach in CC. This would significantly advance individual therapy and enhance patient outcomes. Cuproptosis-related lncRNA targeting is a potential strategy to overcome systemic treatment failures and broaden immunotherapy. These findings might help individuals with CC who are undergoing immunotherapy or chemotherapy treatment. Despite multiple aspects of our verification, the risk model still has some limitations. First, it is a retrospective analysis and there are evitable selection and recall biases. Second, this study lacks in vivo and in vitro experiments to validate the functional roles of the lncRNAs. Third, the model was solely evaluated internally by TCGA, considering genetic heterogeneity, these lncRNAs need to be validated in more public databases, and also a larger sample size is required to obtain conclusive findings, and the prediction model should be practically verified before being applied to clinical patients.

In conclusion, we developed a unique 6 cuproptosis-related lncRNA risk model that might be used as a predictive technique for CC patients. The immune checkpoint inhibitors and chemosensitivity were evaluated, as well as the association between the risk model and the immunological environment. These observations may benefit immune therapy-based interventions and chemotherapy in patients with CC.