Changes in tumor energetics and biosynthetic metabolic pathways are essential for tumor research. In ccRCC, there is a reprogramming of glucose and fatty acid metabolism and changes in the metabolism of the tricarboxylic acid cycle, tryptophan, arginine, and glutamine; for these reasons, the exploration of the mechanisms and factors influencing metabolism in ccRCC are promising [
17]. LncRNAs regulate processes such as energy metabolism in cancer, and a deep understanding of lncRNA-mediated cancer metabolic reprogramming can be beneficial for the diagnosis and treatment of cancer [
18]. Copper increases mitochondrial protein fatty acylation, regulates carbon entry into the TCA cycle, and binds dihydrolipoamide S-acetyltransferase (DLAT) to promote disulfide-dependent aggregation of fatty acylated DLAT [
19]. Ferredoxin 1 (FDX1) is a lipid-acylation effector, contributing to the accumulation of toxic lipid-acylated DLAT and cuproptosis. FDX1-dependent degradation of Fe-S cluster proteins might facilitate cuproptosis [
19]. We, therefore, analyzed lncRNAs associated with ccRCC outcomes, differentially expressed lncRNAs, and cuproptosis-associated lncRNAs and established a risk prediction signature constituted by four genes. According to the risk signature, survival analysis of the high and low groups revealed significant differences. Survival analysis of the four single genes showed that all independently and significantly predicted survival outcomes. Based on the literature, we focused on LINC02154 for in-depth analysis. LINC02154 and the risk signature were analyzed separately in subclinical groupings of age, gender, stage, and grade, and all showed significant differences. TMB can identify patients who may respond to immune checkpoint blockade and discern the type and extent of TMB variants across tumor types and histologies [
20]. High TMB is associated with the appearance of tumor neoantigens on HLA molecules on the surface of tumor cells with a high probability [
21]. Therefore, we speculated that a high TMB might predict a higher effectiveness of targeted therapy. Our TMB analysis of LINC02154 showed a significant difference in TMB between the high and low LINC02154 expression groups, with high LINC02154 expression often predicting higher TMB and high TMB predicting poorer survival. In the same way, we applied the risk signature and found that a high-risk score predicted a high TMB and poor survival. The tumor immune microenvironment is essential for identifying immune modifiers of cancer progression and developing cancer immunotherapies [
20]. We performed a heat map analysis of the immune microenvironment and related assessments of immune function against LINC02154 and found that high expression of LINC02154 changes the immune microenvironment and makes the immune function more active. LINC02154 can be positively correlated with positive markers in immunotherapy and key steps of the immune cycle, which predicts that LINC02154 can play a role in immunotherapy. Analysis of immune checkpoints showed that CD276, CAIR1, CD28, CD44, CD86, CD80, TNFSF4, LGALS9, and PDCD1LG2 were more highly expressed in the high LINC02154 expression group than in the low LINC02154 expression group. We also performed an associated immune microenvironment analysis for the risk signature and found a similar trend to LINC02154. Regarding immune checkpoints, PDCD1, TMIGD2, TNFSF14, TNFRSF18, CD44, LGALS9, and LAG3 expression were higher in the high-risk group than in the low-risk group.Seaman et al. demonstrated that the cell surface protein CD276/B7-H3 is overexpressed in several cancers and tumor-infiltrating vessels; CD276 antibody-medication conjugates (ADCs) equipped with conventional monomethyl auristatin E warheads could kill CD276-positive cancer cells but have little effect on tumor vasculature. Pyrrolobenzodiazepine-conjugated CD276 ADCs can kill cancer cells and tumor vasculature, eradicate large tumors and metastases, and improve OS [
22]. CAIR-1/BAG-3 may serve as a multifunctional signaling protein linking the pathways necessary for activating the EGF receptor tyrosine kinase signaling pathway to the Hsp70/Hsc70 pathway [
23]. CD28 signaling plays a critical role in many biological processes of T cells, including cytoskeletal remodeling, cytokine production, survival, and differentiation and CD28 not only acts as an amplifier of TCR signaling but also can be the source of unique signals and regulates intracellular biochemical processes, including post-translational protein modification and epigenetic changes [
24]. CD44 is a non-kinase transmembrane glycoprotein, and its primary ligand is hyaluronic acid, which can be activated after binding to it, and then activate cell signaling pathways, promote cell proliferation, regulate the cytoskeleton, and enhance cell viability. CD44 is overexpressed in cancer stem cells, and a study suggested that alternatively spliced variants participate in tumor progression [
25]. CTLA-4 is a negative modulator of T cell immune responses, which shares two ligands (CD80 and CD86) with the stimulatory receptor CD28. CTLA-4 captures its ligand from opposing cells by trans-endocytosis [
26]. TNFSF4 was significantly upregulated in lung fibroblasts exposed to stress, and there was a negative correlation between TNFSF4 and tumor shrinkage after treatment with chemotherapeutic agents [
27]. Glioblastoma multiforme-derived exosome LGALS9 can play a significant regulatory role in tumor progression by inhibiting dendritic cell antigen presentation and cytotoxic T cell activation in CSF; if this inhibition is lost, it can lead to long-lasting systemic anti-tumor immunity [
28]. Masugi et al. found a negative correlation between PDCD1LG2 expression and Crohn’s-like lymphoid response in colorectal cancer, suggesting that PDCD1LG2 positive tumor cells may be involved in inhibiting the development of tertiary lymphoid tissues during colorectal carcinogenesis [
29].We performed susceptibility-related analysis and found that differential expression of LINC02154 affected the sensitivity of pazopanib, sorafenib, sunitinib, and temsirolimus. Moreover, there were significant differences in sensitivity to doxorubicin, gemcitabine, sorafenib, and sunitinib between the high- and low-risk score groups. Pazopanib is an oral angiogenesis inhibitor. A randomized, double-blind, placebo-controlled phase III study investigated the safety and efficacy of pazopanib monotherapy in cytokine-pretreated advanced renal cell carcinoma; the authors showed the efficacy of pazopanib in patients with advanced and metastatic RCC reflected improved tumor response and progression-free survival compared with placebo [
30]. Sorafenib was the first multikinase inhibitor approved to treat RCC in the US and Europe [
31]. Several studies demonstrated the efficacy of sunitinib in patients with metastatic RCC [
32‐
35]. A phase III clinical trial showed that temsirolimus had a significantly better treatment effect than IFN-α treatment in RCC patients with poor outcomes in terms of OS, progression-free survival, and tumor response [
36].
In summary, we analyzed the role of LINC02154, a gene associated with cuproptosis-related lncRNAs, in ccRCC. A risk signature composed of four genes for ccRCC containing LINC02154 was constructed, which has clinical value for the outcomes of ccRCC and the judgment of the benefit of targeted therapy and neoadjuvant chemotherapy. We also investigated the proliferation and migration of LINC02154 using cell, CCK-8, EdU, wound-healing, and Transwell assays. We found that the knockdown of LINC02154 inhibited the proliferation and migration of ccRCC cells. Many LINC02154-related data were analyzed using bioinformatics and experimentally verification; nevertheless, there were limitations, Except for TCGA, we did not find the expression information of LINC02154 in the RNA matrix of other patient cohorts, so we could not verify it in other patient cohorts. Besides, more in-depth animal experiments and clinical experiments must be performed to promote the application of LINC02154 in clinical work.