Introduction
The tumor microenvironment (TME) is a complex and dynamic network that plays a crucial role in shaping tumor behavior and influencing patient outcomes. It consists of tumor cells, tumor-associated fibroblasts, immune cells, vascular endothelial cells (ECs), signaling molecules, and the extracellular matrix (ECM).1 These components interact in a way that promotes tumorigenesis, facilitates tumor progression, and drives metastasis.2,3 Tumor cells continuously communicate with both non-tumor cells and non-cellular elements within the TME, adapting to various internal and external stimuli to maintain their malignant characteristics. Among the molecular regulators in the TME, long non-coding RNAs (lncRNAs) have emerged as key players. lncRNAs are RNA molecules longer than 200 nucleotides that do not code for proteins. They are categorized into five types based on their genomic location and orientation: sense, antisense, bidirectional, intronic, and intergenic lncRNAs.4–7
The discovery of tens of thousands of lncRNAs, which outnumber protein-coding genes, has generated significant interest due to their highly specific expression patterns across different cells, tissues, and tumors.8–10 These unique expression profiles suggest that lncRNAs may have crucial roles in cellular processes and disease states, including cancer. Recent studies have revealed that lncRNAs are involved in a wide range of biological processes essential for both normal cellular function and tumorigenesis, such as transcriptional activation and repression, gene imprinting, chromatin modification, and X chromosome inactivation.11–13 lncRNAs can regulate gene expression at multiple levels—transcriptional, post-transcriptional, and translational—exerting profound effects on tumor development and progression. Unlike microRNAs (miRNAs), which typically repress gene expression, lncRNAs employ a variety of mechanisms to modulate cellular functions.14,15 For instance, lncRNAs can directly interact with transcription factors to activate or suppress gene expression, or they can influence chromatin structure by recruiting chromatin remodeling complexes or serving as scaffolds for these complexes.16–18 Some antisense lncRNAs also interact with complementary messenger RNAs (mRNAs) to regulate their splicing, translation, or degradation.19 Beyond these roles, lncRNAs can alter protein localization, regulate protein activity, and participate in larger protein complexes.20,21 Additionally, lncRNAs can function as competitive endogenous RNAs, sequestering miRNAs and thus regulating their availability to bind to target mRNAs.22–24
The role of lncRNAs in the TME is particularly compelling, as these molecules mediate the interactions between tumor cells and their surrounding environment. Through these interactions, lncRNAs contribute to essential processes such as promoting tumor growth, enhancing metastatic potential, inducing angiogenesis, conferring drug resistance, driving metabolic reprogramming, and facilitating immune evasion.25–31 Given their involvement in these processes, lncRNAs have gained attention as potential molecular markers for cancer detection and as novel therapeutic targets. In this review, we aimed to synthesize current knowledge of lncRNAs within the TME, highlighting their diverse functions and potential applications in clinical oncology. We will explore how lncRNAs influence the TME and discuss how these insights may lead to new diagnostic tools and therapeutic strategies. By delving into the multifaceted roles of lncRNAs, this review seeks to lay the foundation for future research and underscore their promise as critical players in cancer biology.
lncRNAs and tumor microenvironment
Tumor cells constantly interact with their surrounding microenvironment during tumorigenesis and development.32 They can influence this environment by secreting various signaling molecules, including lncRNAs.33 These lncRNAs play a crucial role in promoting the proliferation, migration, angiogenesis, and immunosuppressive activities of surrounding non-tumor cells.34–37 This dynamic interaction not only supports tumor growth and spread but also helps tumors evade immune detection.38 Conversely, components within the tumor microenvironment—such as tumor-associated fibroblasts (TAFs), immune cells, and ECs—can also impact tumor cells and other non-tumor cells through lncRNAs.39 These interactions can enhance tumor cell proliferation and migration, contribute to drug resistance, and facilitate further tumor progression.40
lncRNAs serve as mediators in these processes by influencing gene expression and cellular functions at multiple levels.41 For example, lncRNAs secreted by tumor cells can bind to specific receptors on stromal cells, activating signaling pathways that alter the behavior of these cells.42 In turn, these activated stromal cells produce factors that reinforce tumor cell growth and survival, creating a supportive feedback loop.43 lncRNAs also modulate the immune response within the TME by affecting immune cell activity and infiltration. By promoting an immunosuppressive environment, lncRNAs help tumors evade immune detection and destruction.38 Furthermore, lncRNAs regulate angiogenesis in the TME, which is crucial for providing tumors with the nutrients and oxygen necessary for rapid growth (Fig. 1).36 lncRNAs achieve this by regulating angiogenic factors in both tumor cells and ECs. The dual role of lncRNAs in mediating interactions between tumor cells and their microenvironment highlights their significance in cancer biology.39 These interactions are complex and multifaceted, involving not only direct cell-to-cell communication but also the alteration of the ECM and modulation of various signaling pathways.35 Understanding the mechanisms by which lncRNAs orchestrate these interactions opens new avenues for therapeutic intervention.44 Targeting specific lncRNAs that are critical for maintaining the TME could disrupt the supportive network that tumors rely on, potentially inhibiting tumor growth and progression.34 Such an approach could also enhance the efficacy of existing treatments by reducing drug resistance and improving immune responses against the tumor.
In summary, lncRNAs are pivotal regulators in the intricate interplay between tumor cells and their microenvironment. By influencing the behavior of both tumor and non-tumor cells, they contribute to the dynamic nature of the TME and play key roles in tumor development and progression (Table 1).45–47,54,55,59,82,83,87,88
Table 1Roles of long noncoding RNAs (lncRNAs) in the tumor microenvironment
| lncRNA | Tumor type | Role in tumor microenvironment | Mechanism | Ref. |
|---|
| LOC100506114 | Oral squamous cell carcinoma | Transformation of fibroblasts to TAFs | Upregulates GDF10 expression via RUNX2, enhancing tumor cell proliferation and migration. | 45 |
| MALAT1 | Ovarian cancer | Tumor cell migration and invasion | Overexpressed in TAFs promotes epithelial cell migration. | 46 |
| DNM3OS | Esophageal cancer | Radioresistance | Activates PDGFβ/PDGFRβ/FOXO1 pathway to enhance DNA damage response. | 47 |
| PVT1 | Gastric cancer | Angiogenesis | Activates STAT3/VEGFA signaling axis, increasing VEGFA expression. | 54 |
| LINC00173.v1 | Lung squamous cell carcinoma | Angiogenesis and chemoresistance | Acts as a sponge for miR-511-5p, enhancing VEGFA expression and endothelial cell proliferation. | 55 |
| HISLA | Breast cancer | Chemoresistance and aerobic glycolysis | Transferred via TAMs-derived exosomes; disrupts HIF-1α degradation, promoting anti-apoptosis and glycolysis. | 59 |
| CBSLR | Gastric cancer | Hypoxia adaptation | Interacts with YTHDF2, reduces mRNA stability of CBS, and prevents ferroptosis. | 82 |
| RAB11B-AS1 | Breast cancer | Angiogenesis | Upregulated by HIF2, enhances transcription of VEGFA and ANGPTL4 under hypoxic conditions. | 83 |
| CRNDE | Gastric cancer | Promotes chemotherapy resistance and tumor growth | Transferred from M2-polarized macrophages via exosomes, promotes ubiquitination and degradation of PTEN, supports cancer cell survival and proliferation | 87 |
| LINC01614 | Lung adenocarcinoma | Enhances metabolic support for tumor progression | Transferred from TAFs via exosomes, activates NF-κB signaling, upregulates glutamine transporters (SLC38A2 and SLC7A5), enhances glutamine metabolism | 88 |
lncRNAs and TAFs
The relationship between TAFs and tumor cells within the TME is increasingly recognized as a critical factor in cancer progression and therapy resistance (Fig. 2). TAFs, the most abundant stromal cells in the TME, have a profound impact on tumor behavior by modulating various signaling pathways, often via lncRNAs.45–50 These lncRNAs mediate the crosstalk between TAFs and tumor cells, contributing to a microenvironment that promotes tumor growth, invasion, and resistance to therapies (Fig. 3).
Transformation of fibroblasts into TAFs mediated by lncRNAs
A key aspect of TAF-tumor cell interaction is the role of lncRNAs in transforming normal fibroblasts into TAFs, significantly enhancing the pro-tumorigenic capabilities of the TME. For example, the lncRNA LOC100506114 is upregulated in TAFs associated with oral squamous cell carcinoma. This upregulation leads to increased expression and secretion of growth differentiation factor 10 by binding to the transcription factor RUNX2. RUNX2, in turn, drives the transformation of normal fibroblasts into TAFs, which actively promote the proliferation and migration of tumor cells.45
lncRNAs in tumor cell migration and invasion
lncRNAs also play a crucial role in tumor cell migration and invasion, key factors in cancer metastasis. The lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), which is overexpressed in various solid tumors, including ovarian epithelial carcinoma, exemplifies this role. MALAT1 overexpression in TAFs has been linked to enhanced migration of ovarian epithelial cells, indicating that lncRNAs can directly influence the invasive properties of tumor cells by altering the stromal compartment. This suggests that targeting lncRNAs like MALAT1 could disrupt the metastatic potential of cancer cells, offering a promising therapeutic strategy.46
lncRNAs and therapy resistance
TAFs also contribute to the development of resistance to various cancer therapies, a major obstacle in treating malignancies. The lncRNA dynamin 3 opposite strand is upregulated in esophageal cancer cells by TAFs through the platelet-derived growth factor β/platelet-derived growth factor receptor β/forkhead box O1 signaling pathway. Elevated expression of dynamin 3 opposite strand enhances resistance to radiotherapy by modulating the DNA damage response, a key mechanism by which cancer cells survive therapeutic interventions.47 The heterogeneity of TAFs in the TME further complicates tumor behavior and response to treatment. In pancreatic cancer, particularly in patients with platinum-resistant disease, TAFs induce the overexpression of the lncRNA UPK1A-AS1 in tumor cells. This lncRNA promotes non-homologous end joining, a DNA repair pathway that allows pancreatic cancer cells to repair DNA double-strand breaks caused by chemotherapeutic agents like oxaliplatin. Notably, inhibiting UPK1A-AS1 expression in vivo sensitizes tumor cells to oxaliplatin, suggesting that targeting lncRNAs may overcome chemoresistance and improve patient outcomes.50
These findings highlight the multifaceted roles of lncRNAs in mediating interactions between TAFs and tumor cells and their broader impact on the TME. lncRNAs’ ability to modulate key processes such as cell proliferation, migration, invasion, and therapy resistance makes them attractive targets for novel cancer therapies. By targeting specific lncRNAs, it may be possible to disrupt the supportive functions of TAFs, weakening the tumor’s defenses and improving the efficacy of existing treatments. Furthermore, the exploration of lncRNAs in the TME opens new possibilities for biomarker discovery. Given their specific expression patterns across tumor types and their involvement in critical tumor-promoting processes, lncRNAs could serve as valuable biomarkers for early diagnosis, prognosis, and monitoring of treatment responses. Integrating lncRNA profiling into clinical practice could enhance cancer management precision, enabling more personalized and effective therapeutic strategies.
lncRNAs and endothelial cells
Within the TME, vascular ECs play a crucial role in the formation of new blood vessels—a process known as angiogenesis—that supports tumorigenesis, growth, invasion, and metastasis. The activation of these ECs is essential for providing the tumor with the nutrients and oxygen it needs to expand and spread. Recent studies have highlighted that lncRNAs are key regulators of EC activation, significantly contributing to the angiogenic process in various cancers.51–55
In breast cancer, the lncRNA NR2F1-AS1 is positively correlated with the expression of EC markers CD31 and CD34, which are indicators of angiogenesis. NR2F1-AS1 enhances the expression of insulin-like growth factor-1 (IGF-1) in breast cancer cells by binding to miRNA-338-3p. This increase in IGF-1 activates the IGF-1 receptor and the extracellular signal-regulated kinase pathways in human umbilical vein endothelial cells, leading to enhanced EC proliferation, tube formation, and migration.53 This mechanism underscores NR2F1-AS1’s role in driving the angiogenic switch, which is essential for breast cancer progression.
Similarly, in gastric cancer, the lncRNA plasmacytoma variant translocation 1 (PVT1) is significantly upregulated and has been shown to promote tumor angiogenesis by activating the signal transducer and activator of transcription 3/vascular endothelial growth factor A (VEGFA) signaling axis. Upregulation of PVT1 increases VEGFA expression, a key driver of new blood vessel formation, thereby aiding tumor growth and metastasis.54 This suggests that PVT1 plays a crucial role in modulating the angiogenic potential of gastric tumors, positioning it as a potential target for therapeutic intervention.
In lung squamous cell carcinoma, the lncRNA LINC00173.v1 is specifically upregulated, and its overexpression has been linked to increased angiogenesis. LINC00173.v1 acts as a molecular sponge for miR-511-5p, thereby promoting VEGFA expression. This upregulation enhances EC proliferation and migration, further contributing to tumor progression. Notably, targeting LINC00173.v1 with antisense oligonucleotides (ASOs) has been shown to reduce tumor growth and increase the sensitivity of lung squamous cell carcinoma cells to cisplatin, a chemotherapy drug.55 This finding underscores the therapeutic potential of targeting specific lncRNAs to disrupt the angiogenic processes that tumors rely on for survival and resistance to treatment.
Together, these studies highlight that lncRNAs are not only involved in regulating EC function but also act as key drivers of angiogenesis, a process essential for tumor development and metastasis. By modulating signaling pathways such as IGF-1 receptor/extracellular signal-regulated kinase, signal transducer and activator of transcription 3A/VEGFA, and miR-511-5p/VEGFA, lncRNAs like NR2F1-AS1, PVT1, and LINC00173.v1 play pivotal roles in the activation and behavior of vascular ECs within the TME. The potential of lncRNAs as therapeutic targets is particularly evident in their ability to modulate angiogenesis. Inhibiting specific lncRNAs, as shown with LINC00173.v1, can impair tumor growth by disrupting blood supply and enhance the effectiveness of conventional therapies like chemotherapy. Therefore, lncRNAs present a promising avenue for developing novel anti-angiogenic therapies that could complement existing treatment options, offering new hope for patients with aggressive, treatment-resistant cancers. The role of lncRNAs in promoting EC activation and angiogenesis within the TME is a critical aspect of tumor biology. As our understanding of these molecular mechanisms deepens, targeting lncRNAs may provide a powerful strategy for inhibiting tumor progression and improving the efficacy of cancer treatments. Further research into lncRNA-mediated pathways is expected to offer valuable insights into the development of next-generation cancer therapies.
lncRNAs and tumor-associated immune cells
Within the TME, tumor-associated macrophages (TAMs) are the most abundant inflammatory cells, and their presence is strongly correlated with poor prognosis in various cancers.56 TAM plays a crucial role in enhancing tumor malignancy by modulating the expression of lncRNAs in tumor cells. This modulation affects critical cellular processes such as proliferation, motility, invasiveness, and resistance to chemotherapy, driving tumor progression.57–59 Understanding the specific lncRNAs involved in TAM-tumor cell interactions is vital for developing targeted therapies aimed at disrupting these pro-tumorigenic pathways.
lncRNA HISLA
A key mechanism through which TAMs influence tumor cells is by transferring specific lncRNAs via extracellular vesicles. In breast cancer, TAMs have been found to transfer the lncRNA HISLA (hypoxia-induced lncRNA associated) to tumor cells through these vesicles. Inside the tumor cells, HISLA disrupts the interaction between prolyl hydroxylase domain protein 2 and hypoxia-inducible factor (HIF)-1 alpha. This disruption inhibits the hydroxylation and degradation of hypoxia-inducible factor-1 beta, leading to enhanced aerobic glycolysis and increased anti-apoptotic capabilities in the tumor cells. Interestingly, the lactic acid produced during glycolysis by tumor cells further upregulates HISLA expression in macrophages, creating a positive feedback loop between TAMs and tumor cells. This loop not only sustains tumor malignancy but also promotes chemoresistance. Inhibiting HISLA transfer through extracellular vesicles has been shown to reduce glycolysis and chemoresistance in breast cancer cells, highlighting the therapeutic potential of targeting lncRNA-mediated pathways.58
lncRNA ribonuclease P RNA component H1 (RPPH1)
TAMs exhibit functional heterogeneity and can be classified into two main subsets: M1 and M2 macrophages. M1 macrophages are typically associated with antitumor activity, while M2 macrophages promote tumor progression. Tumor cells can manipulate TAM differentiation into these subsets via lncRNAs. In colorectal cancer, the lncRNA RPPH1 is significantly upregulated in tumor tissues. RPPH1 promotes epithelial-mesenchymal transition (EMT) in colorectal cancer cells by interacting with β-tubulin III, a key protein involved in cell motility and stability. Additionally, colorectal cancer cells can package RPPH1 into exosomes, which are then transferred to macrophages. Inside the macrophages, RPPH1 influences their polarization, driving them toward an M2-like, protumor phenotype. This polarization supports the proliferation and metastasis of colorectal cancer cells and contributes to the overall pro-tumorigenic environment in the TME.59
These findings underscore the complex interplay between TAMs and tumor cells, mediated by lncRNAs, within the TME. lncRNAs like HISLA and RPPH1 regulate critical processes such as glycolysis, apoptosis, EMT, and macrophage polarization, emphasizing their importance in tumor biology. By facilitating communication between tumor cells and TAMs, these lncRNAs contribute to a microenvironment that promotes tumor growth, metastasis, and therapy resistance. Given the central role of lncRNAs in these processes, they represent promising therapeutic targets. Disrupting the transfer of HISLA or inhibiting the expression of RPPH1 could impair TAM functions, weakening tumor defenses and enhancing the efficacy of existing treatments. Moreover, targeting lncRNA-mediated signaling pathways may offer a strategy to reprogram TAMs from a protumor M2 phenotype to an antitumor M1 phenotype, further promoting tumor suppression.
lncRNAs and T cells
T cells are essential components of the adaptive immune response against tumors, but their efficacy is often compromised within the TME through various mechanisms regulated by lncRNAs. The lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) has been shown to modulate the expression of immune checkpoint molecules such as programmed death (PD)-ligand 1 on tumor cells. By upregulating PD-ligand 1, NEAT1 inhibits cytotoxic T cell activity, enabling tumor cells to escape immune surveillance.60 Similarly, the lncRNA MALAT1 interacts with miRNAs to influence PD-1 expression on T cells. Elevated MALAT1 levels correlate with increased PD-1 expression, leading to T cell exhaustion and reduced anti-tumor immunity.61 lncRNA Taurine upregulated gene 1 (TUG1) regulates the expression of CTLA-4 on T cells. By enhancing CTLA-4 expression, TUG1 suppresses T cell activation and proliferation, promoting immune tolerance in the TME.62 lncRNA Theiler’s murine encephalomyelitis virus persistence gene 1/NeST is involved in the differentiation of CD8+ T cells into effector cells. Dysregulation of PD1Hi CD8+ T cells impairs their cytotoxic function, reducing their ability to target and eliminate tumor cells effectively.63 Overexpression of LINC00473 in tumor cells has been linked to the suppression of Th1-type immune responses, mediated by cytokine production, resulting in a less effective T cell-mediated anti-tumor response.64 lncRNA interferon-gamma (IFN-γ) antisense RNA 1 enhances the production of IFN-γ in T cells. Downregulation of IFN-γ antisense RNA 1 in the TME can lead to reduced IFN-γ levels, weakening the Th1 immune response and facilitating immune evasion by the tumor.65 The lncRNA Urothelial carcinoma-associated 1 (UCA1) influences T cell metabolism, altering glucose metabolism to reduce T cell proliferation and effector functions, further contributing to an immunosuppressive TME.66 lncRNA Growth arrest-specific 5 (GAS5) regulates the mammalian target of rapamycin signaling pathway in T cells. Reduced GAS5 levels lead to hyperactivation of mammalian target of rapamycin, impairing T cell differentiation and function.67 Finally, lncRNA small nucleolar RNA host gene 16 modulates the expression of chemokines that influence T cell migration into the tumor site. Elevated small nucleolar RNA host gene 16 levels are associated with reduced T cell infiltration, limiting the immune system’s ability to target tumor cells effectively.68
lncRNAs and natural killer (NK) cells
NK cells are essential for the innate immune response against tumors, capable of recognizing and killing tumor cells without prior sensitization. However, their activity can be hindered within the TME through lncRNA-mediated mechanisms. One such lncRNA, NK cell inhibitory ligand-associated lncRNA, is upregulated in certain tumors and interacts with signaling pathways that suppress NK cell activation. This inhibition reduces NK cell cytotoxicity against tumor cells, facilitating immune evasion.69 lncRNA MIR155HG not only affects NK cell maturation but also modulates the expression of activating receptors on NK cells. Abnormal expression of MIR155HG can lead to reduced levels of receptors like natural killer group 2D, which diminishes NK cell-mediated cytotoxicity.70 Similarly, lncRNA GAS5, in addition to its role in T cells, regulates the production of cytokines such as IFN-γ in NK cells. Downregulation of GAS5 in the TME leads to decreased IFN-γ secretion, impairing NK cell function and hindering anti-tumor responses.71 lncRNA deleted in lymphocytic leukemia 1 enhances the production of immunosuppressive cytokines, such as TGF-β, in NK cells. Elevated deleted in lymphocytic leukemia 1 levels contribute to a suppressed NK cell phenotype, reducing their anti-tumor efficacy.72 Beyond its role in inhibiting NK cell activation, MIR155HG also plays a critical role in NK cell maturation. Disruption of its expression can impair normal NK cell development, leading to a reduced population of functional NK cells within the TME.73 lncRNA RPPH1, like its effect on macrophage polarization, can also influence NK cell maturation by modulating the expression of transcription factors essential for NK cell development.74 Additionally, lncRNA HOX transcript antisense RNA (HOTAIR) alters the metabolic state of NK cells by modulating mitochondrial function. Enhanced expression of HOTAIR leads to mitochondrial dysfunction, decreasing NK cell viability and cytotoxicity.75
lncRNAs and other immune cells
Beyond T cells and NK cells, lncRNAs also interact with other immune cells within the TME, such as dendritic cells (DCs) and myeloid-derived suppressor cells (MDSCs), further contributing to immune modulation. lncRNA HOXA transcript antisense RNA myeloid-specific 1 regulates the maturation and antigen-presenting capacity of DCs. Downregulation of HOXA transcript antisense RNA myeloid-specific 1 impairs DC function, reducing their ability to activate T cells and initiate an effective immune response.76 lncRNA DC-specific transcript 1 antisense RNA 1 enhances the expression of co-stimulatory molecules on DCs, promoting T cell activation. Tumors may downregulate DC-specific transcript 1 antisense RNA 1 to evade immune detection.77 lncRNA RUNX family transcriptional regulator OR (RUNXOR) is involved in the expansion and immunosuppressive function of MDSCs. Elevated RUNXOR levels promote MDSC accumulation in the TME, enhancing their ability to suppress T cell activity.78 Similarly, lncRNA small nucleolar RNA host gene 1 facilitates the recruitment and activation of MDSCs by upregulating chemokines and immunosuppressive factors, thereby creating an immunosuppressive TME that supports tumor growth.79
The roles of lncRNAs in regulating various immune cells within the TME present novel therapeutic opportunities. Modulating lncRNAs such as NEAT1, MALAT1, and TUG1 could enhance the efficacy of immune checkpoint inhibitors by restoring T cell activity and overcoming tumor-induced immune suppression. Strategies aimed at increasing the expression of lncRNAs that promote T cell and NK cell activation, such as Theiler’s murine encephalomyelitis virus persistence gene 1/NeST or GAS5, could enhance the immune system’s ability to combat tumors. Inhibiting lncRNAs like RUNXOR and small nucleolar RNA host gene 1 could reduce the immunosuppressive functions of MDSCs and improve the antigen-presenting capabilities of DCs, thus boosting immune surveillance. Targeting lncRNAs that alter the metabolic pathways of T and NK cells, such as UCA1 and HOTAIR, could restore the metabolic fitness and functionality of these immune cells within the TME. Combining lncRNA-targeted therapies with existing treatments, such as chemotherapy, radiotherapy, and immunotherapy, may result in synergistic effects, improving treatment outcomes and overcoming resistance mechanisms.
The interplay between lncRNAs and various tumor-associated immune cells, including TAMs, T cells, NK cells, DCs, and MDSCs, underscores the multifaceted role of lncRNAs in tumor biology. By orchestrating complex signaling networks that regulate immune cell function, lncRNAs contribute to create an immunosuppressive TME that supports tumor growth and resistance to therapy. As research uncovers the diverse functions of lncRNAs, these molecules hold significant promise as targets for innovative cancer therapies aimed at modulating the immune landscape within tumors. Comprehensive understanding and targeted manipulation of lncRNAs-mediated pathways could enhance immune surveillance, slow tumor progression, and improve clinical outcomes for cancer patients.
lncRNAs and the hypoxic tumor microenvironment
Hypoxia is a hallmark of the TME.80 In many cancers, including breast and gastric cancers, tumor cells exhibit high metabolic activity, leading to increased oxygen consumption. Combined with the presence of abnormal blood vessels, this results in insufficient oxygen supply to the tumor cells. In response to these low-oxygen conditions, a range of genes, including lncRNAs, are dysregulated, driving tumor progression and metastasis.81–83
A key discovery in this context is the hypoxia-induced overexpression of the lncRNA CBSLR in gastric cancer cells. Under hypoxic conditions, CBSLR interacts with the RNA-binding protein YTH N6-methyladenosine RNA binding protein 2 (YTHDF2), forming a CBSLR/YTHDF2/cystathionine-β-synthase (CBS) signaling axis. This axis plays a critical role in modulating mRNA stability by enhancing the N6-methyladenosine modification of YTHDF2 and CBS mRNA. This modification reduces the stability of CBS mRNA, leading to the degradation of acyl-CoA synthetase long-chain family member 4, a key enzyme in lipid metabolism. The degradation of acyl-CoA synthetase long-chain family member 4 prevents ferroptosis, a form of programmed cell death driven by iron and lipid peroxidation, thereby promoting the survival and malignancy of gastric cancer cells under hypoxic stress.82
In addition to the CBSLR/YTHDF2/CBS axis, hypoxia also regulates the expression of other lncRNAs through the action of HIFs. HIFs are transcription factors that become stabilized and active in low-oxygen conditions, driving the transcription of genes that help tumors adapt to hypoxia. For example, in breast cancer, HIF2 has been shown to upregulate the expression of lncRNA RAB11B-AS1. This lncRNA enhances the recruitment and activity of RNA polymerase II, which in turn increases the transcription of key angiogenic factors such as VEGFA and angiopoietin-like 4. The overexpression of these factors promotes angiogenesis—the formation of new blood vessels—which is essential for supplying growing tumors with nutrients and oxygen. Moreover, angiogenesis facilitates distant metastasis by providing tumor cells access to the circulatory system, allowing them to spread to other parts of the body.83
These findings underscore the critical role of lncRNAs in helping tumor cells adapt to the hypoxic conditions within the TME. By modulating various signaling pathways and gene expression programs, lncRNAs such as CBSLR and RAB11B-AS1 enable tumor cells to survive, grow, and metastasize in this challenging environment. This adaptation not only supports tumor progression but also poses significant challenges for treatment, as hypoxia-driven changes can contribute to therapy resistance and tumor aggressiveness. The intricate relationship between hypoxia and lncRNA expression highlights the potential for targeting these molecules therapeutically. Disrupting hypoxia-induced signaling pathways mediated by lncRNAs may hinder tumor adaptation to low-oxygen conditions, reducing tumor growth and preventing metastasis. Additionally, targeting lncRNAs involved in hypoxia responses could enhance the effectiveness of existing therapies, particularly in tumors where hypoxia plays a major role in progression and resistance.
lncRNAs and exosomes
Exosomes play a pivotal role in intercellular communication within the TME, with lncRNAs encapsulated in these vesicles serving as key mediators of this interaction. Exosomes are lipid bilayer vesicles ranging from 40 to 150 nm in diameter, capable of transporting a variety of molecular components, including proteins, DNA, mRNA, lncRNAs, and miRNAs. Nearly all eukaryotic cells can secrete exosomes, making them valuable as molecular markers and drug delivery vehicles for disease diagnosis and therapy.84,85 In the TME, lncRNAs are selectively packaged into exosomes, facilitating communication between tumor cells and surrounding stromal cells. This transfer of lncRNAs plays an essential role in regulating tumor biology, including angiogenesis, tumor growth, metastasis, and chemotherapy resistance.86–88 A notable example is the lncRNA CRNDE, which is upregulated in both tumor tissues and TAMs in gastric cancer.
CRNDE is transferred from M2-polarized macrophages to gastric cancer cells via exosomes. Once inside the cancer cells, CRNDE promotes the ubiquitination of phosphatase and tensin homolog by neural precursor cell-expressed developmentally downregulated protein 4-1. This ubiquitination leads to the degradation of phosphatase and tensin homolog, a crucial tumor suppressor, supporting cancer cell survival and proliferation. Notably, silencing CRNDE in these M2-derived exosomes has been shown to reverse the proliferative effects of cisplatin on gastric cancer cells and inhibit tumor growth in cisplatin-treated nude mice xenograft models.87
This example highlights the dual role of lncRNAs in promoting tumor progression and conferring chemotherapy resistance. By mediating the transfer of lncRNAs like CRNDE through exosomes, TAMs contribute to a more aggressive and treatment-resistant cancer phenotype. Targeting these exosomal lncRNAs offers a promising therapeutic strategy to disrupt supportive interactions within the TME, thereby enhancing the efficacy of existing cancer treatments and improving patient outcomes.
The selective packaging of lncRNAs into exosomes and their transfer between cells within the TME emphasize their potential as both therapeutic targets and diagnostic biomarkers. Targeting exosomal lncRNAs could disrupt pro-tumorigenic communication pathways, reducing tumor growth, metastasis, and therapy resistance. Additionally, the presence of specific lncRNAs within circulating exosomes offers a minimally invasive approach to cancer diagnosis and monitoring of treatment responses, enabling more personalized and timely therapeutic interventions.
In lung adenocarcinoma, TAFs similarly modulate tumor progression through the exosomal delivery of lncRNAs. Specifically, TAFs have been found to transfer lncRNA LINC01614 to lung cancer cells via exosomes. Once delivered, LINC01614 directly interacts with AXNA2 and p65, components of the NF-κB signaling pathway. This interaction activates NF-κB, which upregulates the expression of glutamine transporters solute carrier family 38 member 2 and solute carrier family 7 member 5. These transporters enhance glutamine metabolism in lung cancer cells, supporting rapid growth and proliferation. By promoting these metabolic pathways, LINC01614 contributes to the progression of lung adenocarcinoma.88 The ability of exosomes to protect and transport lncRNAs like CRNDE and LINC01614 within the TME underscores their significance in tumor progression. The lipid bilayer of exosomes ensures that these lncRNAs remain stable and functional as they move between different cell types within the tumor, exerting their effects on various aspects of tumor biology. This stability not only facilitates communication between different cell populations in the TME but also allows for the precise regulation of processes such as cell proliferation, survival, and therapy resistance. The growing understanding of exosome-mediated lncRNA transfer in cancer reveals their potential for clinical applications. By targeting specific lncRNAs within exosomes, it may be possible to disrupt the pathological communication networks in the TME, inhibiting tumor growth and overcoming resistance to treatments. Moreover, exosomes themselves offer a promising platform for delivering therapeutic agents, including lncRNA-based therapies, directly to tumor cells, potentially enhancing treatment specificity and efficacy.
Exosomes play a pivotal role in the TME by serving as vehicles for lncRNAs that regulate key processes in tumor progression, such as glucose metabolism, proliferation, and chemoresistance (Figs. 4–6). The protective nature of the exosomal lipid bilayer enables stable delivery of lncRNAs to various cells within the TME, amplifying their impact on tumor development. As research advances, exosome-mediated lncRNA transfer presents a promising avenue for innovative cancer therapies and diagnostic tools.
Clinical application value of lncRNAs in the tumor microenvironment
The abnormal expression of lncRNAs within the TME plays a crucial role in influencing tumor growth and progression. As research into the functions and mechanisms of lncRNAs in the TME has advanced, these molecules have emerged as valuable molecular markers for early cancer detection and as promising targets for therapeutic interventions.89–92 lncRNAs, which regulate various cellular processes, are increasingly recognized for their ability to modulate the behavior of both tumor cells and surrounding stromal cells within the TME. Dysregulation of specific lncRNAs can enhance tumorigenic properties, such as increased proliferation, invasion, and resistance to apoptosis. These aberrant expression patterns are typically not random but closely tied to the specific characteristics and stages of tumor progression.
One of the most promising aspects of lncRNAs is their potential as biomarkers for early cancer diagnosis. Unlike traditional protein markers, lncRNAs are often more specific to certain cancer types and can be detected in body fluids such as blood or urine, making them ideal for non-invasive diagnostic tests.93–95 For instance, circulating lncRNA HOTAIR has been identified as a promising biomarker for the early detection of colorectal cancer, with elevated levels found in the plasma of affected individuals compared to healthy controls.96 Similarly, lncRNA PCA3 is used as a urinary biomarker for prostate cancer, offering higher specificity and sensitivity than the conventional prostate-specific antigen test.97
Early detection is crucial for improving patient outcomes, as it enables timely treatment initiation, which is often more effective in the early stages of cancer. Additionally, the identification of lncRNAs as therapeutic targets opens up new avenues for cancer treatment. Targeting lncRNAs that are overexpressed in the TME could disrupt the supportive interactions between tumor cells and their environment, inhibiting tumor growth and reducing the likelihood of metastasis. Potential therapeutic strategies include the use of antisense oligonucleotides, small interfering RNAs (siRNAs), or small molecules designed to specifically inhibit the function of oncogenic lncRNAs. Furthermore, lncRNAs that are downregulated in tumors could be targeted for reactivation, potentially restoring their tumor-suppressive functions.
Ongoing research into lncRNAs in the TME is also uncovering their role in mediating resistance to conventional therapies.98 Some lncRNAs are involved in regulating drug efflux pumps, DNA repair mechanisms, or apoptotic pathways, contributing to a tumor’s resistance to chemotherapy, radiotherapy, or targeted therapies. By targeting these lncRNAs, it may be possible to sensitize tumors to existing treatments, enhancing their efficacy and overcoming resistance.
For example, UCA1 enhances the expression of the drug efflux pump ABCB1 in breast cancer cells, leading to increased resistance to doxorubicin. Silencing lncRNA UCA1 has been shown to reduce ABCB1 expression and restore doxorubicin sensitivity in breast cancer models.99 NEAT1 facilitates DNA repair in ovarian cancer cells by interacting with BRCA1, contributing to resistance against poly(ADP-ribose) polymerase inhibitors. Inhibition of NEAT1 expression enhances the efficacy of poly(ADP-ribose) polymerase inhibitors in ovarian cancer by impairing DNA repair mechanisms.100 HOTAIR inhibits apoptosis in hepatocellular carcinoma cells by modulating the expression of B-cell lymphoma-2 family proteins, contributing to resistance against cisplatin treatment. Targeting lncRNA HOTAIR can restore apoptotic pathways and sensitize cancer cells to cisplatin.101
These findings highlight the growing importance of lncRNAs as biomarkers in cancer diagnostics. Their stability in body fluids and strong association with tumor characteristics make them valuable candidates for the development of non-invasive diagnostic tests. As research progresses, integrating lncRNA-based biomarkers into clinical practice could revolutionize early cancer detection, leading to earlier interventions and improved prognoses for patients (Table 2).55,87,94–98,102–105
Table 2Potential clinical applications of long noncoding RNAs (lncRNAs)
| Application area | Example lncRNA | Mechanism/Function | Clinical potential | Ref. |
|---|
| Biomarkers for diagnosis | PCA3 | Overexpressed in prostate cancer. | FDA-approved biomarker for early prostate cancer detection. | 94,95 |
| HOTAIR | Highly expressed in glioblastoma. | Non-invasive blood biomarker for glioblastoma diagnosis. | 96 |
| TINCR, CCAT2, AOC4P, BANCR, and LINC00857 | Panel improves gastric cancer diagnosis accuracy (AUC: 0.91). | Non-invasive diagnostic tool for gastric cancer. | 97 |
| ZFAS1, SNHG11, LINC00909, and LINC00654 | Biomarker panel improves colorectal cancer early detection. | Sensitive diagnostic tool for colorectal cancer. | 98 |
| Therapeutic targets | lncARSR | Promotes sunitinib resistance via miR-34/miR-449 competitive binding. | Enhances drug sensitivity in renal cell carcinoma. | 103 |
| FLANC | Supports metastasis in colorectal cancer. | siRNA delivery via nanovesicles inhibits tumor progression. | 104 |
| PKMYT1AR | Maintains cancer stem cells via β-catenin stabilization. | ASOs targeting to reduce tumor growth in non-small cell lung cancer. | 105 |
| LINC00173.v1 | Increases chemoresistance by promoting VEGFA expression in lung squamous cell carcinoma. | Antisense oligonucleotides inhibit tumor growth. | 55 |
| CRNDE | Transferred via TAM-derived exosomes, degrades PTEN. | Targeting reverses cisplatin resistance in gastric cancer. | 87 |
Clinical application of lncRNAs in tumor therapy
The complex nature of the TME has made it clear that therapies focused solely on targeting tumor cells are often insufficient for effective cancer treatment. Recent studies have highlighted the potential of lncRNAs within the TME as both molecular markers for predicting tumor prognosis and as promising targets for therapeutic intervention.99,100 This shift in focus has spurred the development of innovative treatment strategies that utilize technologies such as siRNA, ASOs, CRISPR, and locked nucleic acid to specifically target lncRNAs within the TME.101,102
For instance, in cases of sunitinib-resistant advanced renal cell carcinoma, the lncRNA lncARSR contributes to drug resistance by promoting the expression of AXL and c-MET through competitive binding with miR-34/miR-449. This lncRNA can be packaged into exosomes and transferred to other cells, spreading resistance to sunitinib among tumor cells. Targeting lncARSR with locked nucleic acid technology in mouse models has proven effective in delaying the progression of sunitinib-resistant renal cell carcinoma and restoring the tumors’ sensitivity to the drug.103
In colorectal cancer, the lncRNA FLANC is significantly overexpressed and plays a role in promoting metastasis. High levels of FLANC are linked to poor patient prognosis. Researchers have demonstrated that using nanovesicles to deliver siRNAs targeting FLANC can effectively inhibit tumor growth and metastasis in mouse models, providing a potential therapeutic approach for colorectal cancer.104
The lncRNA PKMYT1AR, highly expressed in non-small cell lung cancer, plays a crucial role in maintaining cancer stem cells by regulating the PKMYT1AR/miR-485-5p/PKMYT1 axis, which inhibits the ubiquitin-mediated degradation of β-catenin by β-TrCP1. Targeting PKMYT1AR with ASOs has significantly reduced tumor growth in mouse models, demonstrating the potential of lncRNA-targeted therapies in cancer treatment.105
These examples underscore the potential of targeting lncRNAs in the TME, not only to reverse drug resistance but also to inhibit tumor growth and metastasis. As research continues to uncover the diverse roles of lncRNAs in cancer, their use as therapeutic targets offers a promising direction for developing more effective cancer treatments. By integrating lncRNA-targeting strategies with existing therapies, it may be possible to enhance treatment outcomes and improve prognosis for patients with various forms of cancer.
Emerging technologies for lncRNA detection and therapeutic delivery
Advancements in molecular biology and nanotechnology have significantly improved strategies for detecting and delivering lncRNA-based therapies within the TME. These emerging technologies aim to improve the specificity, efficiency, and stability of both lncRNA detection and delivery mechanisms, ultimately improving therapeutic outcomes.
Next-generation sequencing has revolutionized the profiling of lncRNAs across various cancer types, enabling high-throughput identification of novel lncRNA biomarkers with increased resolution.106 Recent improvements in single-cell next-generation sequencing techniques have refined the ability to detect lncRNA expression at the individual cell level, offering deeper insights into tumor heterogeneity and lncRNA functions in different cellular contexts.
CRISPR-Cas systems are increasingly tailored for the precise detection of specific lncRNAs in bodily fluids, offering unparalleled sensitivity and specificity. For example, CRISPR-Cas13-based diagnostic platforms can detect low-abundance lncRNAs in liquid biopsies, aiding early cancer detection and monitoring.107 Additionally, innovations in CRISPR-Cas-mediated imaging techniques allow real-time visualization of lncRNA dynamics within live cells, providing valuable information on their spatial and temporal regulation.
Nanopore Sequencing technology has emerged as a powerful tool for real-time lncRNA sequencing, offering insights into their structural variations and post-transcriptional modifications. The development of high-throughput nanopore platforms has improved the resolution and accuracy of lncRNA sequencing, enabling the discovery of novel isoforms and their functional implications in cancer.108 Recent enhancements in nanopore chemistry and signal processing have further improved the fidelity and speed of lncRNA detection, making it a viable option for clinical applications.
Nanoparticle-based delivery systems, including liposomes, dendrimers, and polymeric nanoparticles, have been engineered to deliver lncRNA-targeting molecules such as siRNAs and ASOs directly to tumor cells. These nanocarriers enhance the stability and cellular uptake of therapeutic agents while minimizing off-target effects. Advances in surface modification techniques have enabled the functionalization of nanoparticles with targeting ligands, increasing their specificity toward cancer cells and improving therapeutic efficacy.109 For example, folate-conjugated liposomes have shown enhanced delivery of siRNA against oncogenic lncRNAs in ovarian cancer models.
Synthetic exosomes and exosome-mimicking vesicles represent another promising method for delivering lncRNA-based therapies. These vesicles leverage the natural targeting capabilities and biocompatibility of exosomes to achieve high specificity in delivering therapeutic lncRNAs to tumor cells. Advances in exosome engineering, such as incorporating targeting peptides and optimizing loading techniques, have improved the efficiency and specificity of lncRNA delivery.110 Recent studies have demonstrated the successful delivery of tumor-suppressive lncRNAs using engineered exosomes, resulting in significant tumor growth inhibition in preclinical models.
CRISPR/Cas9-based delivery systems are also being utilized to edit or modulate lncRNA expression within tumor cells, offering a precise method to alter lncRNA function. Innovations in CRISPR delivery, including the use of viral vectors, lipid nanoparticles, and cell-penetrating peptides (CPPs), have enhanced the efficiency and specificity of genome editing in cancer cells. Breakthroughs such as inducible CRISPR systems allow for temporal control over lncRNA editing, reducing potential off-target effects and improving therapeutic safety.111 For example, lipid nanoparticle-encapsulated CRISPR/Cas9 has successfully targeted oncogenic lncRNAs in liver cancer models, demonstrating significant therapeutic potential.
Cell-penetrating peptides have been employed to facilitate the delivery of lncRNA-targeting molecules into cancer cells, enhancing therapeutic efficacy. CPPs such as TAT and penetratin have been conjugated with siRNAs and ASOs to improve cellular uptake and stability. Recent advancements in CPP design, including the incorporation of stimuli-responsive elements, have allowed for controlled release of therapeutic agents in the TME, further increasing the precision of lncRNA-based therapies.112 Recent studies have shown that CPP-mediated delivery of lncRNA inhibitors can effectively suppress tumor growth and metastasis in various cancer models.
The integration of cutting-edge molecular biology techniques and nanotechnology has significantly advanced the detection and therapeutic delivery of lncRNAs in cancer. These emerging technologies not only improve the precision and efficiency of lncRNA-based interventions but also pave the way for personalized, targeted cancer therapies. Ongoing research and development in this field hold great promise for improving cancer diagnosis, prognosis, and treatment outcomes.
Limitations of this review
While this review provides a comprehensive overview of the roles of lncRNAs in the TME, several limitations must be acknowledged. The review primarily focuses on studies published up to 2023, meaning that recent advancements beyond this period may not be fully captured. Although multiple cancer types are discussed, the vast heterogeneity among cancers means that some specific interactions between lncRNAs and the TME may not be thoroughly covered. While significant mechanisms are highlighted, the complex and multifaceted roles of lncRNAs in cancer biology still require further elucidation through more detailed mechanistic studies. The translation of preclinical findings into clinical applications is still in its early stages, and this review may not fully address the challenges or progress in clinical trials involving lncRNA-targeted therapies. Additionally, emerging technologies for lncRNA detection and delivery are rapidly evolving, and the review may not encompass the latest innovations or their potential applications. Addressing these limitations in future research will provide a more nuanced and detailed understanding of the intricate roles of lncRNAs in cancer and their potential as therapeutic targets.
Conclusions and future directions
Aberrantly expressed lncRNAs within the TME are emerging as critical players in tumor growth, progression, metastasis, and drug resistance. These lncRNAs influence a wide range of cellular processes, including the regulation of gene expression, modulation of cell signaling pathways, and interactions with various components of the immune system and ECM. Their role in shaping the complex interactions between cancer cells and their microenvironment makes them vital for sustaining tumor development. Additionally, lncRNAs regulate processes such as EMT, angiogenesis, immune evasion, and the maintenance of cancer stem cells, all of which contribute to tumor aggressiveness and therapy resistance. As research continues to explore the roles and mechanisms of lncRNAs in the TME, it holds great potential for uncovering new insights into tumor pathogenesis and progression. This expanding knowledge could pave the way for developing novel therapeutic strategies specifically targeting lncRNAs, offering more precise and effective cancer treatments. For example, targeting lncRNAs involved in immune evasion could enhance immunotherapy efficacy, while inhibiting lncRNAs that promote metastasis may help prevent cancer spread. Despite these promising prospects, the clinical application of lncRNAs as therapeutic targets remains in its early stages, with several significant challenges still to overcome. One major hurdle is the complexity and diversity of lncRNAs’ functions, which require a thorough understanding of the context-specific mechanisms through which they operate. Furthermore, developing robust and specific strategies for lncRNA knockdown or inhibition is essential to avoid off-target effects that could lead to unintended consequences. Identifying suitable delivery systems for targeting lncRNAs within the TME is also critical, as these molecules are often difficult to deliver effectively due to their size and structure.
Future research should focus on overcoming these challenges by elucidating the diverse mechanisms through which lncRNAs exert their effects, optimizing methods for specific and efficient lncRNA inhibition, and designing innovative delivery systems that can target lncRNAs within the TME with high precision. Addressing these challenges will be crucial for translating the potential of lncRNAs into tangible clinical benefits, ultimately improving outcomes for cancer patients. With continued progress, lncRNAs could become valuable therapeutic targets, revolutionizing cancer treatment and offering new hope for patients facing advanced and drug-resistant cancers.
Declarations
Acknowledgement
The authors have utilized the highly esteemed software, Biorender, to create the figures for this manuscript. BioRender.com (2025). Retrieved from https://www.biorender.com/.
Funding
This work was supported by the Bashkir State Medical University Strategic Academic Leadership Program (PRIORITY-2030).
Conflict of interest
Ilgiz Gareev has been an editorial board member of Gene Expression since February 2025. Irina Popova is an employee of the medical center at PJSC Novatek and the medical center of LLC “Sherwood Premier” in Moscow, Russia.
Authors’ contributions
Study conception, study design (OB), data acquisition, analysis, and interpretation (EM, CW), drafting of the manuscript (OB), critical revisions of the manuscript (IG), writing – review & editing (IP), and supervision (OB). All authors agreed on the journal to which the article would be submitted, gave the final approval to the version to be published, and agreed to take responsibility for all aspects of the work.