The mortality rate of malignant tumors ranks second among human diseases, which seriously threaten human health (1). Immunotherapy can activate immune cells and enhance antitumor immune responses, changing the treatment mode of tumors. However, most patients either fail to respond to immune checkpoint inhibitors (ICIs) or develop drug resistance. The tumor immune microenvironment plays a pivotal role in tumor immunity and largely determines the effectiveness of immunotherapy. To maintain malignant growth and rapid proliferation of tumors, cancer cells consume a great amount of nutrients, for instance, oxygen, glucose, glutamine, and amino acids, resulting in nutrient deficiency and hypoxia in the tumor microenvironment (TME). As tumor cells compete with immune cells for nutrients in the TME, the activation and proliferation of immune cells are inhibited (2–4). Furthermore, tumor cells can influence immune and stromal cells within the TME, resulting in an immunosuppressive environment that facilitates tumor immune escape. Therefore, understanding how tumor metabolic reprogramming influences the TME can enhance immunotherapy efficacy and identify new therapeutic targets.

Non-coding RNAs (ncRNAs) occupy for approximately 60% of transcriptional output in human cells (5). Although they do not encode proteins, they play indispensable roles at the transcriptional and post-transcriptional levels by combined with DNA, RNA, and proteins to regulate gene expression and protein function. A diverse array of ncRNAs establishes an intricate network that influences numerous biological functions and signaling pathways (5). The disorder of non-coding RNA is closely related to malignant tumors, nervous system diseases, cardiovascular diseases, and autoimmune diseases. Notably, dysregulation of ncRNAs has been associated with all malignancies studied to date and affects all major tumor biomarkers (6, 7). As the most abundant category of non-coding RNAs, long non-coding RNAs (lncRNAs) can influence tumor metabolic reprogramming by regulating key enzymes, transporters, and related signaling pathways in tumor metabolism. Metabolites in the process of tumor metabolic reprogramming, such as lactic acid and free cholesterol, can impair the activation and function of antitumor immune cells, for example, T and NK cells, and promote the polarization of macrophages to the M2 subtype, eventually forming a tumor immunosuppressive microenvironment. Therefore, lncRNAs affect TME remodeling through tumor metabolic reprogramming (8, 9). In this paper, we introduced the role and relationship of lncRNAs in tumor metabolic reprogramming and tumor microenvironment remodeling and summarized the prospects of lncRNAs as future anti-tumor therapeutic targets and prognostic biomarkers.

LncRNAs are an important category of non-coding RNA that are greater than 200 nucleotides in length (10). Based on their localization in the genome, lncRNAs can be classified into sense lncRNAs, antisense lncRNAs, intronic lncRNAs, and intergenic lncRNAs. Sense lncRNAs overlap with the positive strand RNA of neighboring genes, and the transcription direction is the same as that of neighboring genes. Antisense lncRNAs are opposite to sense lncRNAs. Antisense lncRNAs overlap with the negative strand RNA of neighboring genes, and its transcription direction is opposite to that of neighboring genes. Intronic lncRNAs are produced in the intron region within genes by different splicing methods. Intergenic lncRNAs, also known as “lincRNAs,” are located between two genes and usually do not overlap with known protein-coding genes (11, 12). In addition, lncRNAs has strong tissue specificity and cell specificity. In one study, the expression of hundreds of novel lncRNAs was shown to be cell type-dependent (13). Previous investigations have suggested that lncRNAs affect the occurrence and progression of tumors via regulation of the epigenome, gene transcription, or protein translation (14, 15).

Some lncRNAs mediate the recruitment of chromatin remodeling complexes or serve as scaffolds for chromatin remodeling complexes (16, 17). LncRNA HOTAIR had been shown to regulate chromatin remodeling, thereby promoting breast cancer metastasis (18). LncRNA DIRC3 in the nucleus affect the local chromatin structure and activate the transcription of tumor suppressor IGFBP5 (19). LncRNA LINC00261 is involved in phosphorylation of ataxia telangiectasia mutated protein (ATM) and DNA damage of lung adenocarcinoma cells, slowing cancer progression (20). LncRNAs can also activate or repress gene expression by binding to or removing transcription factors (21). Some antisense lncRNAs specifically bind to complementary mRNAs to regulate gene splicing, translation, or degradation at the post-transcriptional level (22). LncRNA REG1CP binds the helicase FANCJ to the promoter of the neighboring gene REG3A86, promoting growth of colorectal cancer (23). LncRNA-p21 can bind to heterogeneous ribonucleoproteins, increasing transcription of neighboring gene CDKN1A and synthesis of P21 protein (24). Other lncRNAs can alter protein localization, regulate protein activity, or serve as components of protein complexes. For example, a HIF-1α anti-sense lncRNA, HIFAL introduces the PKM2/PHD3 complex into the nucleus by binding to heterogeneous nuclear ribonucleoprotein F (hnRNPF) to enhance the production of hypoxia-inducible factor-1 (HIF-1) and promote breast cancer. Therefore, HIFAL is also a target for treatment of breast cancer (25, 26). LncRNA LUCAT1 inhibits phosphorylation of annexin A2, further inhibiting the degradation of ANXA2-S100A10 heterotetramer (AIIT) and promoting cancer development (27). In neuroblastoma, lncRNA LINC02525 interacts with ribosomal protein RPL35. They then specifically activated the translation of E2F1, advancing neuroblastoma (28). There are also lncRNAs that can cleave and produce small RNAs precursors or serve as competitive endogenous RNAs that act as “sponges” for miRNAs (29). Several studies have indicated that lncRNAs play indispensable roles in tumor growth, metastasis, angiogenesis, drug resistance, cell metabolic reprogramming, and the induction of immunosuppression through a variety of complex mechanisms (30–32) ( Figure 1 ).

Body metabolism includes glucose, lipids, amino acids, and the metabolism of other nutrients. The metabolism of various substances affects each other, and metabolic signaling pathways interact with each other to form a complex metabolic network. The metabolic patterns of cancer cells are quite different from those of normal cells. The environment of the cancers has special characteristics, such as hypoxia, acidity, oxidative stress, and nutrient deficiency. To better adapt to this environment, tumor cells must adjust their metabolic pathways to meet the needs of their various life activities, which is called metabolic reprogramming (33). On the one hand, metabolic reprogramming of cancer promotes tumorigenesis by facilitating rapid proliferation, survival, invasion, and metastasis. On the other hand, as the tumor progresses, tumor cells acquire more mutations and alterations, resulting in enhanced metabolic reprogramming, which in turn accelerates tumor growth, proliferation, and development.

Metabolic and functional changes of tumor cells mainly include: 1) Healthy cells rely on mitochondria to oxidize glucose and release energy, while most tumor cells supply themselves with energy through glycolysis, which has a relatively low energy yield. This metabolic property of tumor cells is also known as the Warburg Effect. Since glycolysis has relatively little capacity, cancer cells must maintain their vital activities by upping their glucose intake. Many cancer cells do this by activating glucose transporters. In addition, tumor cells undergoing metabolic reprogramming use transcription factors such as HIF-1α and c-Myc to up-regulate glycolytic enzyme activity, thereby increasing glycolytic efficiency. At the same time, the conversion of glucose to lactate, rather than to pyruvate increases, which means that less pyruvate enters the mitochondria, leading to inhibition of the tricarboxylic acid cycle (TCA) pathway (34, 35); 2) Since pyruvate is overconsumed in the glycolytic pathway, glutamine is used to supplement important metabolites in TCA. As complementary substrate for TCA, glutamine continuously produces NADH, FADH2, and electrons for adenosine triphosphate (ATP) production through oxidative phosphorylation of the mitochondria. Cancer cells depend on c-Myc transcription factor to increase the expression of glutamine transporter and glutamine lyase, leading to increased cellular uptake and utilization of glutamine (36). Glutamine can produce glutamic acid under the catalysis of glutaminase, and glutamic acid can be converted into alanine, aspartate and other amino acids. At the same time, glutamic acid can be used as a substrate to synthesize α-ketoglutaric acid, continuing to provide fuel for TCA (37); 3) In terms of lipid metabolism, in metabolically reprogrammed cancer cells, most acetyl-CoA used for lipid synthesis comes from citrate produced by the TCA in the mitochondria. In the cytoplasm, citrate can be converted back to acetyl-CoA and lipid synthesis occurs (38); 4) anabolism, including nucleotide synthesis, nonessential amino acid synthesis, lipid synthesis, and hexosamine synthesis, is upregulated, which consumes large amount of energy; 5) The pentose phosphate pathway (PPP) is upregulated, which maintains cellular redox homeostasis and downregulates the generation of reactive oxygen species. As a rate-limiting enzyme in the PPP, glucose-6-phosphate dehydrogenase (G6PD) is frequently elevated in human malignancies, which in turn leads to the production of precursors for nucleotide and lipid synthesis (39–41) ( Figure 2 ).

The TME is a complex microenvironment for tumor cells to survive and is made up of tumor cells, stromal cells, fibroblasts, infiltrating immune cells, and the secreted products and extracellular matrix of the corresponding cells. Immune cells are key players in shaping inhibitory microenvironments. In the TME, immune cells have distinct functions compared to normal tissues. For purpose of satisfying the need of rapid proliferation of tumor cells, they undergo metabolic reprogramming, which causes the TME to show ion homeostasis imbalance, acidity, hypoxia, increased lactate, decreased glucose concentration, nutritional competition, and changes in the secretome. Remodeling of the TME induces the metabolic reprogramming of immune cells, which changes their functions. They exhibit an attenuated inflammatory response or enhanced inhibitory function, assisting immune escape from the tumor. Therefore, TME remodeling caused by tumor metabolic reprogramming is the basis for the functional transformation of immune cells and is particularly critical for the proliferation and metastasis of cancer cells.

The most obvious feature of the TME is the constantly changing in its constituents, particularly in the later stages of cancer development. Tumor-derived cytokines, chemokines, and even metabolic conditions (pH, oxygen levels, and nutrients) affect the function of immune cells in TME (42). In the early stages of oncogenesis, the TME is an immune-activated microenvironment with high proinflammatory signals, and immune cells are prone to show a pro-inflammatory phenotype. In the process of cancer growth and metastasis, the TME changes into an immunosuppressive environment step by step, with low oxygen, low pH, low glucose accumulation, high fatty acid accumulation, low amino acid accumulation, high adenosine accumulation, and high lactic acid accumulation, and immune cells are inclined to show an inhibitory phenotype (43). Unlike other microenvironments in the body, TME changes are mainly dominated by tumor cells rather than by the body itself, which is largely out of the control of the body. In this sophisticated, constantly changing, and uncontrollable microenvironment, the roles of various non-tumor cells are also complex and dynamic. For example, immune cells differentiate into subsets with different phenotypes, metabolic characteristics, and functions, which play anti-tumor or pro-tumor roles, and further change the TME through their own metabolism.

It is not only tumor cells that require macronutrients and energy to meet their own needs for proliferation and metastasis. For purpose of accomplishing the proliferation, differentiation, and effector functions of various immune cells, the immune system requires a large number of similar nutrients for biosynthesis. In addition, the metabolic modes of immune cells in the activated and effector states are markedly distinguishable from those in the resting state. For example, the metabolism of naïve T cells is usually quiescent, mainly through oxidative phosphorylation to produce energy. Once differentiated into effector T-cells, they lean primarily upon glycolysis for energy production (58). Neutrophils rely mainly on aerobic glycolysis and the pentose phosphate pathway to provide energy. Glycolysis is a primary metabolic pathway in activated B lymphocytes (59). However, the oxidative phosphorylation of fatty acids is a major metabolic pattern in both regulatory T cells and M2 macrophages (60). After the tumor initiates metabolic reprogramming, the function of the immune system is impaired by the competitive uptake of nutrients, for instance, glucose, fatty acids, glutamine, and amino acids. Investigations have shown that cancer cells can compete for glucose uptake and enhance glycolysis to inhibit the function of tumor-infiltrating lymphocytes (TILs), limit glucose consumption by TILs, and ultimately result in T cell exhaustion and tumor immune evasion. Notably, not only changes in tumor metabolic patterns but also metabolites from tumor reprogramming can affect the phenotype and function of immune cells. The accumulation of lactic acid can inhibit the function of T and NK cells. Moreover, lactic acid upregulates the expression of PD-L1 on the surface of tumor cells and mediates T cell exhaustion by binding to the PD-1 receptor on the surface of T cells (61). In addition, reprogramming of tumor lipid metabolism can lead to increased cholesterol levels in the TME, which can upregulate the expression of inhibitory immune checkpoints, such as PD-1 and LAG-3, on the surface of T cells, leading to an increase in the number of exhausted T cells. Similarly, immune cells become less functional and proliferative and are more susceptible to apoptosis (62) ( Figure 3 ).

Furthermore, existing research has confirmed that lncRNAs are closely related to the innate immune system (63). The innate immune system serves as the first line of defense against pathogens and relies on a surveillance system involving neutrophils, macrophages, natural killer cells, and dendritic cells. LncRNAs have been shown to function through modular domains, regulating gene expression and modulating pathogen response pathways by interacting with chromatin, RNA, and proteins (64).

They can engage in T cell development, activation, differentiation, function, and cancer immunology by binding specifically to the epidermal growth factor receptor (EGFR) or inducing the expression of cell surface phenotypes, as well as suppressing Treg-mediated immune evasion in hepatoma carcinoma cells (HCCs) (65, 66). Additionally, lncRNAs play a critical role in macrophage differentiation, recruitment, polarization, and functionality. They regulate macrophage differentiation by modulating ACVR1B (a key factor in macrophage differentiation) to activate the TGF-β pathway (67), or by influencing the calcium-dependent kinase PNCK triggered by Ca2+, which leads to macrophage recruitment and angiogenesis. Similarly, lncRNAs are involved in the reprogramming of normal fibroblasts (NF) to cancer-associated fibroblasts (CAFs). They participate in this process through exosomes delivery, gene knockout, and inhibition of autophagy-lysosomal degradation, which further modulates the metabolism and chemotherapy resistance of CAFs (68, 69).

Latest researches have indicated that lncRNAs upregulate the expression of key enzymes and transporters in tumor metabolic reprogramming through a variety of mechanisms and regulate related signaling pathways, eventually leading to changes in the TME (70–75) ( Table 2 ). Therefore, lncRNAs may reprogram the tumor immune microenvironment by regulating tumor metabolism.

It has been shown that TAMs secrete lncRNA HISLA via extracellular vesicles. HISLA can reduce the hydroxylation and degradation of HIF-1α via blocking the interaction between PHD2 and HIF-1α, which promotes glycolysis and lactate accumulation in tumor cells. Accumulated lactic acid can further prompt TAMs to secrete HISLA. Thus, HISLA silencing mediated by RNA interference has great potential to interrupt tumor glucose metabolic reprogramming, which will further weaken TME immunosuppression induced by tumor metabolic reprogramming and help restore immune cell function. The use of aptamer-siRNA chimeras to mediate specific HISLA knockdown in TAMs to abort tumor glucose metabolism remodeling and restore antitumor immune functions warrants further investigation. Similarly, lncRNA HIFAL can promote HIF-1α transactivation complex assembly and glycolytic metabolism. Inhibition of HIFAL can weaken tumor glycolysis and reduce the tumor energy supply and glycolytic products, weakening the inhibitory effect of tumor metabolic reprogramming on immune cells (122). This is a potential new target for antitumor therapy.

In addition to lncRNAs involved in regulating tumor metabolism, the immune checkpoint signaling axis regulates tumor metabolic reprogramming. PD-L1 expression in cancer cells can activate the Akt-mTOR signaling axis, enhance glycolysis, prompt glucose competition between the tumor and T cells, and increase lactate production. Notably, lactate accumulation, glucose stress, and PH value decrease in the TME also upregulate PD-1 expression, which promotes tumor immunosuppression and immune evasion (61). Immune checkpoint inhibitors inhibit glycolysis to a certain extent and weaken immune suppression; however, the overall therapeutic efficiency of immunotherapy remains limited. Whether anti-lncRNA-targeted metabolic therapy combined with immunotherapy can further improve the effects of tumor treatment and enhance antitumor immunity is worth exploring in the future. Theoretically, the inhibition of dysregulated lncRNA-mediated reprogramming of tumor metabolism could restore its suppressive effects on immune cells. However, it is undeniable that, given the physiological situation, these metabolic processes also contribute to the activation of the immune system, and the interruption of these metabolic processes will also influence the activation of immune cells and anti-tumor immunity. Therefore, identifying the best method to accurately target disordered tumor metabolic reprogramming is a direction for our future research.

Targeting lncRNAs operate precise biological functions through various mechanisms, notably as guides, scaffolds, and decoy molecules, among others. A profound understanding of these multifaceted roles is crucial for the development of highly efficient targeting strategies (157). However, the clinical implementation of therapeutic targeting of lncRNAs has been constrained by several unresolved issues. Firstly, the low level of conservation among species for lncRNAs poses a significant hindrance to numerous research models. Furthermore, the subcellular localization of lncRNAs varies significantly between human and mouse embryonic stem cells, and their stability also differs markedly between the two species (158). This implies the potential irrelevance of findings from other organisms to human clinical contexts consequently (159). Moreover, lncRNAs enable targeting multiple genes, which increases the potential probability of off-target effects when attempting to target them. It is imperative that clinical trials meticulously consider both the likelihood and the extent of these effects, aiming to mitigate them in the safest manner possible. Notably, these intricacies may not be fully elucidated through animal studies alone is a formidable challenge in lncRNA-targeting strategies (160). To mitigate the aforementioned issues, incorporating transcriptome-wide association study (TWAS) could serve as an effective complementary approach to genome-wide association studies, enhancing our ability to identify genes linked to traits like diseases and elucidating the intricate regulatory interactions among them (161). For lncRNAs, the genetic association signal about transcript abundance within a particular tissue can be juxtaposed against the signal associated with a specific disease, thereby facilitating the validation of the disease’s causal relationship. Employing these strategies enables the identification of lncRNAs that hold the greatest relevance for experimental investigation. Ideally, these lncRNAs should be tested using humanized models to gain a deeper insight into their underlying mechanisms of action (160, 162).

Existing tumor markers have poor sensitivity and specificity. However, reliable biomarkers for predicting the prognosis of patients with cancer are still lacking. Considering the high stability of lncRNAs in blood and their resistance to nuclease degradation, circulating lncRNAs appear to be reliable and promising prognostic biomarkers. Circulating lncRNAs have been used as reliable diagnostic and prognostic markers in various cancers, including liver, colorectal, gastric, and prostate cancers (163). In particular, the available biomarkers for predicting the response to immunotherapy are limited. Given the role of lncRNAs in mediating the immunosuppressive TME, circulating lncRNAs are expected to be complementary markers for predicting the efficacy of immunotherapy. Further studies are needed to explore the feasibility of using lncRNAs as prognostic markers in clinical practice.

Tumors initiate metabolic reprogramming to support their rapid proliferation, altering the TME. This triggers competition for nutrients between tumor and immune cells, leading to metabolic changes in immune cells that promote an immunosuppressive microenvironment and tumor immune evasion. LncRNAs impact TME remodeling via these metabolic shifts. Targeted lncRNA therapy aims to overcome immunotherapy resistance and drug tolerance in tumor patients, presenting a novel anti-tumor strategy.