Thyroid carcinoma (THCA), a prevalent malignancy of the endocrine system, can be classified based on its origin and degree of differentiation. This includes papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, poorly differentiated thyroid carcinoma, and anaplastic thyroid cancer (Haddad et al., 2022). Differentiated thyroid carcinomas encompass papillary, follicular, medullary, and mixed carcinomas. Papillary thyroid carcinoma is the most predominant subtype of THCA, constituting over 90% of all cases (Cabanillas et al., 2016). THCA is becoming more prevalent worldwide (La Vecchia et al., 2015). An epidemiological study revealed that THCA has grown to the ninth largest incidence of cancer in the population, the incidence rate is rising at a rate of 3%, and the incidence in women is three times higher than that in men (Bray et al., 2018).

Clinical manifestations of THCA may include the development of abnormal thyroid tumors, varying degrees of dyspnea, dysphagia, hoarseness, lymphadenopathy, and cervical pain. Treatment modalities for THCA typically involve surgical intervention, iodine radiation therapy, and thyroid hormone suppression therapy (Cabanillas et al., 2016). The detection rate of THCA, which has low invasion, slow growth, and low mortality, has increased year by year with the advancement of medical technology and social and economic development. Risk factors linked to the development of THCA include exposure to excessive radiation, abnormalities in glycolipid metabolism, fluctuations in thyroid hormone levels, unhealthy lifestyle choices, hereditary factors, and other variables (Fiore and Vitti, 2012; Borena et al., 2014; Albi et al., 2017). Studies have revealed an increase in morbidity and mortality in advanced THCA, and long-distance cancer cell dissemination can severely damage patients’ quality of life and health (Im et al., 2017). Biomarkers reflecting genetic, protein, and metabolomic alterations have been identified to improve tumor detection, diagnosis, prognosis, and monitoring. Despite this, there has been limited research focused on the relationship between THCA and biomarkers. Investigating THCA biomarkers is crucial for enabling personalized prognosis and treatment.

The role of immunotherapy in the field of oncology is gaining increasing attention from researchers due to its successful treatment of a number of tumor types, leading to a change in the way patients with advanced cancer are treated (Gong et al., 2021). However, due to the high level of malignancy and resistance in THCA, patients have poor prognoses, and viable treatment options are limited. The identification of biomarkers has the ability to both predict the outcome of pharmacological immunotherapy and, to a certain extent, avoid the side effects associated with conventional immunotherapy. Individualized therapy that incorporates anticipated biomarkers and immunotherapy may be a promising treatment approach for patients.

In the human body, copper serves a variety of functions in cells that help maintain cellular homeostasis at low concentrations (Tsvetkov et al., 2022). Studies have demonstrated that the disturbance in the equilibrium of copper homeostasis result in cellular toxicity accumulation, leading to abnormal cell death (Kawahara et al., 2021). Mitochondrial respiration may be necessary for the recently identified copper-dependent regulation of cell death. Copper binds directly to lipids in the tricarboxylic acid (TCA) cycle, causing acylated-protein aggregation and loss of iron-sulfur cluster proteins, which leads to proteinotoxic stress and cell death through various mechanisms, including apoptosis, oxidative stress, and autophagy (Tsvetkov et al., 2022). Tumor development is abnormally correlated with copper and iron levels (Mou et al., 2019). Previous research has demonstrated that ferroptosis is associated with immune cell infiltration in THCA patients, indicating essential genes for developing prognostic models for genetic traits and prognosis prediction (Lin et al., 2021). A novel type of cell death known as cuproptosis has gradually risen to the attention of academics as a potential future research focus due to its effects on cancer and development. According to clinical research, imbalance in copper homeostasis can play a significant role in the development of endometrial cancer (Atakul et al., 2020). Breast cancer stem cells may experience endoplasmic reticulum and oxidative stress, elicit damage-related molecular patterns, and are more susceptible to macrophage phagocytosis, all of which can be caused by the endoplasmic reticulum targeting the copper (II) complex (Kaur et al., 2020). Controlling the breakdown of the copper transport-related protein ATP7A reduces intracellular copper accumulation, prevents excessive oxidative stress and iron death, and decreases colorectal cancer cell growth (Gao et al., 2021). The clinical potential of cuproptosis in cancer is significant. Studies have revealed elevated serum copper levels in THCA patients, indicating a possible link between copper level alterations and the development of THCA (Shen et al., 2015). Additionally, it has been demonstrated that the cuproptosis-related gene FDX1 influences the survival prognosis of THCA patients (Zhang et al., 2022). However, research on cuproptosis is in its early stages, and its exact mechanism of action is not yet fully understood.

Abnormal copper buildup has the potential to hinder the expression and production of epigenetic elements such as microRNA and lncRNA. Research on cells exposed to copper has revealed that microRNA and circRNA can modulate mitochondrial dysfunction and the TCA cycle, regulate crucial proteins like FDX1, ATP7A, and LIPT1, and alter the mitochondrial membrane potential, as illustrated in Figure 1A (Hsu et al., 2019; Chen et al., 2022; Jin et al., 2022; Liao et al., 2022). Long non-coding RNAs (lncRNAs) are transcripts longer than 200 nucleotides that originate from the genome and exhibit diverse biological activities. As a ceRNA competitive binding microRNA that controls gene expression, it also impacts critical physiological and pathological mechanisms, such as autophagy, development, apoptosis, and cell cycle (Dykes and Emanueli, 2017).

LncRNAs have caught the attention of numerous researchers due to their potential to act as biomarkers and play a multi-functional role in malignancies. LncRNA remains a hot research topic since it is essential for tumor cellular metabolism, apoptosis, invasion, and chemosensitivity (Peng et al., 2017). Furthermore, LncRNAs have the ability to selectively target and control critical proteins involved in immune responses. This can indirectly or directly alter immune cell infiltration in the tumor microenvironment. Overexpression of lncRNA AC003092.1 in glioblastoma has been found to decrease miR-195 function, regulate TFPI-2 expression, improve sensitivity to mortizolomide, and aid tumor cell inhibition (Xu et al., 2018). Expression of lncRNA-NEAT1 predicts prognosis and is an independent predictive factor for overall patient survival in prostate cancer patients (Wen et al., 2020). LncRNA-HOTAIR is extensively expressed in tissues, sera, and cell lines of patients with THCA. Suppression of LncRNA-HOTAIR can prevent tumor cell proliferation, migration, and invasion, ultimately improving patient prognosis (Liu et al., 2020). However, more research is needed to fully understand how lncRNAs affect THCA.

Cuproptosis-related lncRNAs may play a significant role in clinical diagnostic and therapeutic implications for THCA (Zhang et al., 2022). To date, the precise mechanism through which cuproptosis-related lncRNAs affect THCA and predictive models based on cuproptosis genes and immune cells in the THCA’s immune infiltrated microenvironment remain unexplored. To the best of our knowledge, this is the first study to analyze the therapeutic targets linked to THCA from lncRNAs connected to cuproptosis. In this study, we used bioinformatic analysis to analyze cuproptosis-related lncRNAs of THCA patients and their biological and immunological activity and involvement in predicting the prognosis of patients with THCA. Figure 1C depicts the precise operational procedures of this study. The study thoroughly and methodically analyzes the probable link between cuproptosis and lncRNAs in THCA, discusses the potential relevance of cuproptosis-related lncRNAs as prognostic and immunotherapeutic markers for THCA patients, and provides guidance and evidence for the clinical treatment of THCA.

THCA is the most prevalent and rapidly increasing malignant tumor of the endocrine system. Despite a higher overall survival rate than other malignancies, there was a difference in the 5-year relative survival rate of patients with THCA between China and the United States (Miller et al., 2019). The pathophysiology of THCA remains incompletely understood and requires a multimodal treatment approach. Accurately predicting the prognosis and survival of patients with THCA is crucial for preventing and managing the disease. This requires the development of trustworthy THCA risk profiles. The non-protein-coding RNA family, known as lncRNA, has attracted much attention in recent years (Tan et al., 2021). Numerous studies have revealed that lncRNAs may play a significant role in tumorigenesis and development, the immune system, and inflammatory gene expression, making it one of the key targets for the treatment of THCA. The emergence of modern genomics and bioinformatics has made it possible to uncover the role of lncRNA in THCA, supported by the gradual maturation of detection technologies (Kong et al., 2019; Wang et al., 2019; Tang D et al., 2022). According to Pang et al.'s study, lncRNA DUXAP8 was significantly expressed in THCA, enabling it to serve as a target of miR-20b-5p. This interaction regulated the expression of proteins such as SOS1, c-myc, and CCND1, consequently inhibiting abnormal proliferation of thyroid cancer cells (Pang and Yang, 2021). Additionally, the knockdown of LINC00311 has been shown to suppress the development, proliferation, migration, and invasion of spheroids in THCA cells in vitro through the miR-330-5p/TLR4 pathway (Gao et al., 2020). Cuproptosis is a distinct type of cell death caused by excessive intracellular copper accumulation, which results from FDX1-mediated mitochondrial protein toxicity stress dependent on the mitochondrial TCA cycle (Duan and He, 2022; Tang R et al., 2022). Modulating intracellular copper levels and oxidase activity can partially mitigate mitochondrial respiratory deficits, but these solutions require further clinical testing (Ghosh et al., 2014). Nevertheless, the precise mechanism of action of cuproptosis-related lncRNAs and their relationship with THCA requires further research.

Seven lncRNAs associated with cuproptosis were identified as prognostic factors for THCA in this study, including AC108704.1, DIO3OS, AL157388.1, AL138767.3, STARD13-AS, AC008532.1, and PLBD1-AS1. By applying co-expression, univariate, and multivariate Cox analyses, the study found that these prognostic features were independent of other typical clinical features. Using ROC curves, survival analysis, and line maps, the high- and low-risk groups of THCA patients could be accurately predicted based on their risk scores, demonstrating that these lncRNAs were reliable prognostic factors. Moreover, the study showed that the prediction model based on cuproptosis-related lncRNAs can accurately predict the prognosis of THCA patients, considering factors such as age, stage, and risk score.

The possibility of DIO3OS as a biomarker for hepatocellular, lung, and pancreatic malignancies has been demonstrated (Cui et al., 2019; Wang et al., 2020; Zhang M et al., 2021). Inhibiting DIO3OS expression by blocking the DIO3OS/let-7d/NF-B2 axis, which lowers the expression of ki-67 and PCNA and reduces cancer cell viability (Wang et al., 2021). Triiodothyronine (T3) insufficiency results from increased deiodinase 3 (D3) activity caused by DIO3OS inactivation, which affects metabolic function by altering thyroid hormone signaling pathway (Chen et al., 2021). DIO3OS, as a cis-transcription element, can influence the expression of nearby genes at the transcription site. Additionally, it can target miR-18a-3p, miR-1913, and miR-266-3p to exert chromatin localization function and obstruct protein binding in the DNA region (Chen et al., 2021). AL138767.3 has been identified as a prognostic biomarker for glioma instability (Maimaiti et al., 2021). A 645 bp non-coding RNA (ncRNA) named STARD13-AS found on chromosome 13q13.1 was connected to numerous tumor progressions. RNA binding proteins such as NANOG, OTX2, POU5F1, SOX17, TBXT, and others can directly interact with STARD13-AS, which is highly expressed in enterocyte progenitor cells. It may also facilitate the interaction of the cohesins or the enhancer and mediator complex (Zhang and Chambers, 2019; Zhang et al., 2021). When STARD13-AS expression was controlled, LoVo and SW620 cells expressed higher levels of E-cadherin and N-cadherin, which reduced the growth and spread of colorectal cancer cells (Nasrallah et al., 2014; Yang et al., 2019). By blocking miR-9-5p, STARD13-AS inhibits the proliferation and migration of prostate cancer cells, thereby slowing tumor growth (Chen et al., 2019). STARD13-AS may engage in the TCA cycle to regulate proteins involved in mitochondrial activity and energy substrate oxidation through a process similar to cuproptosis by inhibiting miR-19a-3p (Pinto et al., 2017). As an autophagy-related lncRNA, PLBD1-AS1 has been demonstrated to be significantly correlated with the prognosis of hepatocellular carcinoma and may be linked to TP53BP1 and CHMP4B (Deng et al., 2021). PLBD1-AS is overexpressed in breast and liver cancer cells, which is mostly accomplished by physiological and pathological processes, such as cell metabolism, cell proliferation, apoptosis, and immune response (Luo et al., 2022; Safarzadeh et al., 2022). While these lncRNAs have been demonstrated to impact the development of various cancers, further research is necessary to determine their specific effects on THCA. There is no evidence to suggest that AC108704.1, AL157388.1, and AC008532.1 have any involvement in cancer.

According to the PCA results, seven cuproptosis-related lncRNAs could discriminate between groups at high and low risk. Additionally, GO and KEGG analyses revealed that, based on biological processes, such as protein synthesis, transport, angiogenesis, apoptosis, enzyme regulation, and immune response, cuproptosis-related lncRNAs may be directly related to THCA formation through the TGF-β and PISK-Akt signaling pathways. By verifying GEO databases, the relationship between lncRNA and THCA was further confirmed. Several studies have highlighted the significance of GDF6, RGS4, FGF7, GLIS1, SST, and MT3 in predicting patient prognosis (MacDonald et al., 2020; Puig-Domingo et al., 2014; Nikiforova et al., 2019; Ji et al., 2020; Fan et al., 2022; Li et al., 2022). DPP4 facilitates epithelial-to-mesenchymal transformation and thyroid cancer cell metastasis by interacting with α4 and β1 integrin subunits to activate the transcription of the TGFB1 protein via the FAK/AKT/C-JUN/TGF-β signaling pathway (He et al., 2022). Moreover, the regulation of thyroid cancer cell proliferation and tumor growth can be achieved through the competition for miR-34a binding via the PI3K/AKT signaling pathway by downregulating miR-34a levels downstream of the hepatocyte growth factor receptor proteins by reducing lncRNA XIST expression (Liu et al., 2018).

During tumor development, immune cell infiltration in the tumor microenvironment changes. The relationship between immune-related functions, TMB, and risk ratings in patients with THCA was investigated. Various studies have linked T-cell follicular helper cells, T-cell regulation, and B-cell memory to adverse effects in THCA (Koida et al., 2007; Xie et al., 2020; Wang et al., 2022). Single-cell analysis of GEO databases has revealed that regulatory T cells, CD8⁺ T cells, monocytes, B cells, dendritic cells, and neutrophils are crucial components of THCA tissue. Additionally, tumor metastasis frequently occurs in lymph nodes. By controlling the invasion and response of immune cells, the interaction between tumor invasion-related cells and the host immune system is achieved (Garnier et al., 2019).

The high-risk group exhibited higher expression levels of B cells, dendritic cells, T helper cells, Th1 helper cells, and tumor-infiltrating lymphocytes, as indicated by the results of immune infiltration analysis. Given that this result is highly consistent with previous findings, it is likely that the high-risk group will have a poorer prognosis than the low-risk group. These results suggest that cuproptosis, especially macrophages and T cells, may have a significant role in regulating the tumor microenvironment. In addition, the ssGSEA score revealed that patients in the high-risk group exhibited more pronounced immunological traits, including antigen presentation, immune response, para-inflammatory response, and T cell response, all of which are associated with the THCA tumor immune microenvironment and immune response suppression. The high-risk group had higher immunoscores and lower tumor purity scores compared to the low-risk group, as indicated by the estimated, immune, and stromal scores.

By preventing T cell expression, LAG3 and CTLA4 play crucial roles in the immunological escape mechanism of THCA cells (Park et al., 2022). CD80, CD86, and CD28 can elicit immunosuppression by preventing B and T cell activation and proliferation. Nevertheless, this requires the cooperative action of TNFRSF18, TNFRSF8, and BTLA (Wu et al., 2021). Interestingly, the ICOS, LAG3, IDO2, TNFRSF18, CTLA4, CD80, and BTLA groups exhibited superior performance in the low-risk group than in the high-risk group. Using the TIDE algorithm to assess the clinical response of THCA patients to immune checkpoint inhibitor (ICI) treatment, we found that the TIDE score of the high-risk group was significantly higher than that of the low-risk group. This higher score indicated a higher probability of immune escape and limited response to ICI treatment, leading to a shorter survival time for patients in this group. Based on the aforementioned results, we suggest that cuproptosis-related lncRNAs are involved in several crucial physiological processes, dependent on multiple targets and pathways, and closely related to THCA tumor immunity, as shown in Figure 15. A follow-up experimental study is required to comprehend better the connection between cuproptosis-related lncRNAs and immunological performance.

Finally, we investigated the drugs’ sensitivity and used the pRRophetic package to identify effective drugs for THCA immunotherapy. Clinical trials have demonstrated that the EGFR inhibitor, lapatinib, can modestly increase the survival time of breast cancer patients and exhibit antitumor efficacy (Goss et al., 2013). Lapatinib can reduce THCA cell proliferation and improve medication sensitivity by controlling the phosphorylation of ERK and AKT (Ohno et al., 2022). Dasatinib, by activating Src signaling, c-Src, and Lyn proteins, causes cell cycle arrest and cell death in THCA fractions and acts as an anti-THCA equilibrium agent (Chan et al., 2012). However, there is insufficient evidence in the current study to determine whether these anticancer drugs are more beneficial for the low- or high-risk groups, and further research is required to identify their precise mechanisms.

The study successfully identified clinical characteristics that affect THCA patients’ prognosis and established a predictive risk model that categorizes patients into low- and high-risk groups based on cuproptosis-related lncRNA. The prognostic model showed a strong association with THCA prognosis. The correlation between THCA and immunological response, inflammatory response, cell proliferation, etc., was shown by immune infiltration, GO, and KEGG assays based on cuproptosis-related lncRNAs. However, this study has some limitations, although it contributes new theoretical research approaches to investigating the process of cuproptosis and gaining new insights into clinical practice for THCA patients. The lack of survival prognosis information on cuproptosis-related lncRNAs in the GEO dataset made it challenging to gather additional data to support the prognostic model. The validity of cuproptosis-related lncRNAs needs to be confirmed through comprehensive clinical trials since the study’s findings are based on publicly available databases, and there was a lack of data on clinical samples, leaving the subject still unclear. Nonetheless, we discovered a potential link between cuproptosis-related lncRNA and THCA that could serve as a basis for further in vitro and clinical experiments to validate the association.