Unraveling the advances of non-coding RNAs on the tumor microenvironment: innovative strategies for cancer therapies.

Introduction

Cancer therapies face numerous challenges, with the TME significantly impacting treatment efficacy. The TME includes diverse cell types, extracellular matrix components, and biomolecules that support tumor growth and affect its response to therapies. Even if initial treatments are effective, the TME can drive tumor recurrence and drug resistance, severely limiting outcomes. Hypoxic conditions within the TME, for example, can increase the expression of angiogenic factors such as vascular endothelial growth factor (VEGF), promoting new blood vessel formation and further supporting tumor growth [ 1 – 3 ]. Thus, a deep understanding of the TME’s role in cancer progression and the discovery of biomarkers that accurately reflect disease status and predict therapeutic responses are crucial for advancing new treatment approaches [ 4 , 5 ].

The physiological and pathological roles of ncRNAs in various diseases, particularly cancer, are gaining increased attention. These ncRNAs, including miRNAs, lncRNAs and circRNAs, are crucial for regulating cell growth, differentiation, and tumorigenesis [ 6 – 8 ]. For instance, miR-124 can enhance the efficacy of ovarian cancer immunotherapies by inhibiting Treg cell function through targeting MCT1 [ 9 ], while lncRNA SNHG16 promotes breast cancer growth by modulating miR-218-5p [ 10 ]. Exosomes, serving as vital carriers of ncRNAs, play a role in cellular communication and significantly influence the TME [ 11 , 12 ]. In gliomas, exosomes enriched with miR-3184-3p from cerebrospinal fluid not only boost glioma progression but also induce M2-like macrophage polarization, enhancing tumor aggression [ 13 ].

Compared to other biomolecules such as proteins and DNA, ncRNAs exhibit distinct advantages. Traditional protein biomarkers often face challenges due to their complexity and detection difficulties, and they may lose specificity due to post-translational modifications [ 14 ]. In contrast, ncRNAs, owing to their relatively small molecular size and stability, are more easily detected by high-throughput sequencing technologies and demonstrate higher specificity and sensitivity [ 15 ]. Additionally, while genomic DNA changes provide critical information about genetic variations, they often fail to fully explain epigenetic regulatory mechanisms and their impact on disease [ 16 ]. On the other hand, ncRNAs directly participate in gene expression regulation, providing a more precise reflection of cellular states and disease progression [ 17 ].

In addition to directly influencing tumor progression, ncRNAs hold significant promise for cancer diagnosis and prognosis. Risk models based on exosome-associated lncRNAs effectively predict survival outcomes in breast cancer [ 18 ]. These molecules also show potential as therapeutic targets, particularly in addressing chemotherapies resistance. For instance, in triple-negative breast cancer (TNBC), circulating circPS-MA1 activates the miR-637/Akt1/β-catenin (cyclin D1) axis, promoting tumorigenesis, metastasis, and migration [ 19 ]. Moreover, ncRNAs participate in alternative splicing, impacting gene expression patterns and cancer biology [ 20 – 22 ]. Notably, ncRNAs are not confined to a single cancer type; they are prevalent across various malignancies, including hepatocellular carcinoma, ovarian cancer, and oral squamous cell carcinoma (OSCC), each with distinct mechanisms of action [ 23 – 25 ].

As our understanding of ncRNAs and their interactions with the TME grows, numerous studies are exploring the application of this knowledge in developing new cancer therapies. Researchers aim to inhibit or reverse tumor progression by modulating ncRNA levels or modifying their transport pathways [ 26 – 29 ]. Although challenges like delivery efficiency, specificity, and toxicity persist [ 30 – 32 ], ncRNA-based treatments remain a promising avenue in cancer research. Thus, ncRNAs and related mechanisms offer fresh insights into cancer treatment and pave the way for personalized medicine [ 33 – 36 ]. This review examines the structural and functional features of ncRNAs, their roles in the TME, and highlights recent advancements in cancer therapies.

Structural and functional regulatory features of different NcRNAs

MiRNAs

MiRNAs, approximately 22 nucleotides long, are single-stranded ncRNA molecules. They regulate gene expression by binding to specific sequences in the 3’ untranslated region or coding region of target mRNAs. MiRNAs control gene expression at the post-transcriptional level, influencing processes such as cell proliferation, differentiation, apoptosis, and metabolism [ 37 ]. Gaining insight into miRNA functions and their intricate regulatory networks is crucial for developing novel cancer therapies. Below, we detail the structural characteristics of miRNAs and how they functionally regulate gene expression.

The process of miRNA biosynthesis involves several key steps: generation of primary miRNA (pri-miRNA), processing of precursor miRNA (pre-miRNA), and the functional realization of mature miRNA (Fig. 1 ). Pri-miRNAs are long RNA molecules transcribed from DNA by RNA polymerase II. These transcripts contain one or more imperfect hairpin structures crucial for further processing [ 38 ]. In the nucleus, Drosha, an RNase III enzyme, along with its cofactor DGCR8, forms a complex that recognizes and cleaves these hairpins, producing pre-miRNAs about 60–90 nucleotides long with a distinctive 2-nucleotide 3’ overhang [ 39 , 40 ]. Pre-miRNAs are then exported to the cytoplasm by the XPO5 protein. In the cytoplasm, Dicer, another RNase III enzyme, processes pre-miRNAs into double-stranded RNA molecules around 19–22 nucleotides long [ 41 , 42 ]. One strand, typically the 5p or 3p arm, is chosen as the guide strand and associates with an Argonaute protein to form the RNA-induced silencing complex (RISC). The other strand, known as the passenger strand, is often degraded [ 43 ].

The resultant RISC complex uses the mature miRNA as a guide to recognize and bind to target mRNAs [ 44 ]. This binding can lead to degradation, destabilization, or translational repression of the target mRNA, based on the level of complementarity between the miRNA and its target, along with other influencing factors. Consequently, miRNAs can precisely control protein synthesis post-transcriptionally, impacting gene expression regulation in numerous biological processes such as development, cell differentiation, and disease conditions [ 45 ].

The function of miRNAs primarily occurs through base pairing between their seed regions, typically the 2nd to 8th nucleotides, and the target mRNA. This interaction alone can lead to measurable inhibition of the target. Even with a short seed region, pairing can still be effective if there is an adenine opposite the first position of the miRNA [ 46 ]. Moreover, miRNAs can simultaneously affect multiple mRNA targets, and there is potential for synergistic interactions among different miRNAs, adding to the complexity of miRNA networks [ 47 ]. Additionally, some miRNAs can regulate targets in unconventional manners, such as by relying solely on 3’ complementary pairing [ 48 ].

The biogenesis of miRNAs is strictly controlled, with each step—from transcription to processing and translocation—being influenced by numerous factors. Specific sequence features, like bulges and mismatches in miRNA precursors, can boost Dicer processing efficiency [ 49 ]. Various RNA-binding proteins (RBPs) play roles in regulating the structure and stability of miRNA precursors [ 50 ]. Notably, miRNAs do not solely function in the cytoplasm; they can also be found in the nucleus or other organelles, performing additional regulatory functions, such as transcriptional regulation [ 51 ]. Additionally, research has uncovered a process known as target RNA-directed miRNA degradation (TDMD). In this phenomenon, highly complementary target RNAs can recruit the ZSWIM8 E3 ubiquitin ligase via the AGO2 complex, resulting in the ubiquitination and proteasomal degradation of AGO2, and ultimately leading to miRNA destruction [ 52 ].

Fig. 1 MiRNAs undergo a complex synthesis process. They are also subject to intricate processing steps. Ultimately, they are either degraded or mature into functional miRNAs. These mature miRNAs carry out diverse biological functions through various mechanisms. The image was drawn via Figdraw with permission

LncRNAs

LncRNAs are RNA molecules exceeding 200 nucleotides in length. Despite not coding for proteins, they carry out numerous essential biological functions within cells [ 53 ]. This section will explore the structural characteristics of lncRNAs and their roles in cellular processes (Fig. 2 ).

The structural features of lncRNAs underpin their functional diversity. At the secondary structure level, lncRNAs can form complex conformations like hairpin, stem-loop structures, and pseudoknots via base pairing. These structures enhance the morphological diversity of lncRNAs and contain conserved short modules crucial for their specific functions. For instance, SINEUP lncRNAs feature conserved short structural modules that boost translational enhancement [ 54 ]. Such modules show dynamic changes between the nucleus and cytoplasm and can interact with various proteins and RNA molecules, forming a complex regulatory network. An example is the interaction between TERRA lncRNAs and LSD1, where the TERRA-LSD1 complex increases Rad51AP1 enrichment at telomeres through phase separation (the process by which certain proteins and RNAs spontaneously form distinct, membrane-less compartments within cells to regulate biochemical activities and cellular functions), boosting R-loop formation and supporting telomere maintenance in the ALT (Alternative Lengthening of Telomeres) pathway [ 55 ]. This phase separation mechanism offers new insights into how lncRNAs regulate gene expression through physical aggregation.

The structural complexity of lncRNAs is evident in their ability to form high-level structures across multiple levels. For instance, studies on the TubAR lncRNA have demonstrated its capacity to promote microtubule assembly by binding to specific proteins. TubAR lncRNAs interact with α- and β-microtubule protein heterodimers via specific secondary structures, stabilizing microtubules and supporting cerebellar myelination and neuronal activity [ 56 ]. Moreover, NAP-seq technology has identified a variety of novel structured ncRNAs, such as stably expressed linear intronic RNAs (sliRNAs) and misRNAs located within miRNA spacer regions. These napRNAs exhibit dynamic changes in response to different stimuli and stages of differentiation [ 57 ]. Consequently, the structural diversity of lncRNAs underpins their broad spectrum of biological functions.

LncRNAs have diverse roles in gene expression regulation. They influence transcriptional regulation, epigenetic modification, microRNA sponging, and splicing regulation [ 58 ]. In transcriptional regulation, lncRNAs can alter chromatin structure by binding to DNA, affecting gene expression. An example is LINC00673, which changes chromatin accessibility in breast cancer cells, impacting gene expression [ 59 ]. Epigenetically, lncRNAs participate in histone modification and DNA methylation [ 60 ], crucial for cancer development. Some lncRNAs act as miRNA sponges, reducing the suppression of target mRNAs. For instance, NEAT1 lncRNA serves as a sponge for miR-377-3p in lung cancer, boosting the expression of the oncogene E2F3 [ 61 ]. LncRNAs also play a role in the selective splicing of pre-mRNAs. MALAT1, for example, influences the splicing of SRSF1 targets, increasing anti-apoptotic splicing variants and activating the mTOR pathway through the regulation of S6K1 splicing, contributing to hepatocellular carcinoma progression [ 62 ].

CircRNAs

CircRNAs are ncRNAs characterized by their covalently closed loop structures. Initially considered as splicing errors or by-products of RNA transcription, circRNAs have gained attention due to advancements in bioinformatics and high-throughput sequencing technologies. Recent studies have revealed that circRNAs display distinct spatiotemporal and spatial expression patterns within cells. They are linked to numerous biological processes, such as tumorigenesis and immune response [ 63 , 64 ]. Unlike linear mRNAs, circRNAs do not have a 5’ cap or a 3’ poly(A) tail, making them more resistant to exonuclease degradation [ 65 ]. CircRNAs primarily arise from the reverse splicing of pre-mRNAs, where the 3’ end of one exon connects to the 5’ end of another, forming a closed loop. This process can produce various circRNA types, such as exon-only circRNAs (ecoCIRNAs), exon-intron circRNAs (EIciRNAs), and intron-only circRNAs (ciRNAs) [ 66 , 67 ].

The biogenesis of circRNAs is regulated by both cis-acting elements, such as reverse transcription complementary sequences, and transacting factors, including RBPs and spliceosomal factors [ 68 ]. The presence or absence of these regulatory factors, along with their spatial distribution and temporal expression patterns, influences the likelihood of reverse splicing events, impacting the production of specific circRNAs [ 69 ]. For instance, some circRNAs require specific RBPs for their formation, whereas others depend on particular repeat sequences within introns [ 70 ].

These structural features enable circRNAs to perform multifarious functions. They can act as miRNA sponges, adsorbing miRNA molecules to release target mRNAs and upregulate their expression. CircRNAs also interact with proteins to form complexes, influencing transcription or translation processes. Some circRNAs are capable of being translated into functional peptide chains or proteins [ 71 , 72 ]. Research indicates that this translation can occur in an internal ribosome entry site (IRES)-dependent or independent manner [ 73 ]. For instance, circ-SHPRH translates into the SHPRH-146aa protein via the IRES mechanism, which helps inhibit tumor growth [ 74 ]. Additionally, certain circRNAs can modify gene expression by directly interacting with the genomic DNA of their host genes [ 75 ].

Dysfunction of circRNAs is widely reported in cancer and plays a significant role in the development of various malignant tumors [ 76 ]. For instance, in colorectal cancer, circRNA_0000392 acts as a sponge for miR-193a-5p, leading to increased PIK3R3 expression and promoting tumor progression [ 77 ]. Additionally, circRNAs are involved in regulating the TME. An example is hsa_circ_0136666, which promotes gastric cancer progression and immune evasion by modulating the miR-375/PRKDC axis and PD-L1 phosphorylation levels [ 78 ]. These findings indicate that circRNAs perform crucial biological functions in cells and may serve as promising diagnostic markers and therapeutic targets [ 79 ].

In summary, circRNAs are crucial for gene expression regulation due to their unique ring structure and specific expression patterns (Fig. 2 ). As scientific research progresses, we will gain a deeper understanding of circRNAs. This will help uncover more details about their mechanisms and promote the development of novel circRNA-based therapies. These advancements are expected to transform the field of precision medicine.

Fig. 2 LncRNAs and circRNAs have distinct synthesis and processing pathways. Once mature, these RNAs execute various biological functions via different mechanisms. The image was drawn via Figdraw with permission

TME

Compositions and functions of the TME

The TME is a complex ecosystem (Fig. 3 ) comprising multiple cell types, the extracellular matrix (ECM), blood vessels, and various soluble factors that collectively support tumorigenesis, progression, and metastasis [ 80 ]. Within the TME, tumor cells interact with immune cells, fibroblasts, endothelial cells, and stromal cells, forming a dynamic and highly heterogeneous network [ 81 ]. Tumor-associated macrophages (TAMs) foster tumor growth, angiogenesis, and immunosuppression. Regulatory T cells (Tregs) also contribute to tumor immune evasion by suppressing the function of effector T cells [ 82 ]. Moreover, the ECM in the TME not only provides physical support for tumor cells but also influences their behavior through the release of growth factors and cytokines [ 83 ].

Immune cells in the TME play a crucial role in tumor development. NK cells and CTLs can recognize and kill tumor cells, thereby inhibiting tumor growth [ 84 ]. Conversely, TAMs and MDSCs suppress anti-tumor immune responses by secreting immunosuppressive factors, which promotes tumor progression [ 85 ]. Additionally, fibroblasts, particularly CAFs, enhance tumor cell proliferation and migration through the secretion of extracellular matrix components and growth factors [ 86 ]. These intricate cellular interactions not only influence tumor biology but also significantly impact the therapeutic response of tumors [ 87 ].

Characterization of the TME

TAMs can be categorized into M1 and M2 types. M1 TAMs exhibit pro-inflammatory and anti-tumorigenic properties, while M2 TAMs display immunosuppressive and pro-tumorigenic effects [ 88 , 89 ]. Moreover, metabolic stress within the TME results in metabolic reprogramming of both tumor and immune cells, which further increases TME heterogeneity [ 90 ]. Such metabolic changes impact tumor cell survival and proliferation and also facilitate tumor immune evasion by altering immune cell function [ 91 ].

A notable feature of TME is its resistance to cancer therapies. Tumor cells and immunosuppressive cells compete for essential nutrients and metabolites, thereby hindering the function of immune effector cells and diminishing the effectiveness of immunotherapies [ 92 ]. Hypoxic areas within the TME also cause adaptive changes in both tumor and immune cells, further boosting tumor resistance [ 93 ]. For instance, hypoxia prompts tumor cells to increase PD-L1 expression, which can suppress T cell activation and function [ 94 ]. These characteristics underscore the importance of therapeutic approaches that target the TME to enhance treatment efficacy through its remodeling [ 95 ].

Therapeutic strategies for the TME

Therapeutic strategies aimed at the TME focus on reshaping it to restore or boost anti-tumor immune responses. Recent in-depth studies of the TME have led to the identification of numerous biomarkers. These biomarkers can predict patient responses to treatments and serve as potential therapeutic targets [ 96 ]. For instance, circulating tumor DNA (ctDNA) is useful for monitoring the mutational burden and treatment effectiveness of tumors, aiding in the selection of personalized therapies [ 97 ]. Additionally, ncRNAs, including miRNAs, lncRNAs and circRNAs, play a significant role in regulating the TME. They can also serve as novel biomarkers and therapeutic targets [ 98 ].

Nanomedicine, as an emerging therapeutic tool, enhances the efficacy of immunotherapies by improving the TME through metabolic reprogramming [ 99 , 100 ]. It allows targeted delivery of drugs to the tumor site, where they can modulate the metabolic state of both tumor and immune cells, helping to reverse the immunosuppressive microenvironment [ 101 , 102 ]. Some nanoparticles achieve this by inhibiting the glycolytic pathway—a series of enzymatic reactions in which glucose is converted into lactate to produce energy (ATP)—in tumor cells, thereby reducing lactate production and subsequently decreasing immunosuppression. Inhibiting the glycolytic pathway, which is abnormally activated in cancer cells and supports their rapid proliferation, compromises cancer cell metabolism, weakens their survival advantage, and enhances anti-tumor immune responses by lowering the levels of lactate that inhibit immune cell function. As a result, these nanoparticles, which are specifically designed to target and disrupt the metabolic vulnerabilities of tumor cells, offer a promising strategy to augment therapeutic efficacy in cancer treatment [ 103 , 104 ]. Additionally, certain nanomedicines can boost anti-tumor immune responses by enhancing the function of immune cells, further improving treatment outcomes [ 105 ]. These approaches provide new hope for overcoming immunosuppression within the TME.

Fig. 3 Multiple components such as immune cells, cytokines, extracellular matrix, and peripheral vasculature co-regulate the TME. The image was drawn via Figdraw with permission

Regulation of different NcRNAs in the TME and therapeutic potentials

MiRNAs

In the TME, miRNAs play a crucial role in regulating the behavior of cancer cells via diverse mechanisms. MiR-15a, for instance, is low expression in pancreatic ductal adenocarcinoma; its upregulation can curb tumor progression by targeting BMI-1, thus suppressing cell proliferation and epithelial-mesenchymal transition (EMT) [ 106 ]. Meanwhile, miR-1247-3p enhances angiogenesis in bladder cancer by targeting FOXO1, speeding up tumor growth [ 107 ]. Beyond cancer cells, miRNAs influence immune cells, fibroblasts, and other stromal cells, affecting tumor progression. Hypoxia-induced downregulation of miR-1275 impairs natural killer (NK) cell function, facilitating immune evasion in pancreatic cancer [ 108 ]. MiR-6794-5p boosts tumor growth by promoting M2-type macrophage polarization [ 109 ]. Moreover, miR-1246 regulates TAMs polarization through the NOD-like receptor pathway, advancing colorectal cancer [ 110 ]. MiR-146a curtails ovarian tumor growth by targeting immunosuppressive neutrophils and boosting CD8 + T-cell infiltration [ 111 ]. Conversely, miR-1246 also supports ovarian tumor growth by modulating M2-type macrophage polarization [ 112 ]. MiR-4488 triggers M2 polarization in macrophages and fosters hepatic metastasis of pancreatic neuroendocrine tumors via RTN3/FABP5-mediated fatty acid oxidation [ 113 ]. MiR-5100 accelerates head and neck squamous cell carcinoma metastasis by enhancing exosome-mediated activation of CAFs [ 114 ]. The hsa_circ_0009092/miR-665/NLK signaling pathway restrains colorectal cancer by attracting TAMs [ 115 ]. These findings highlight the multifaceted and intricate roles of miRNAs in the TME. CAFs are pivotal in this environment, and miRNAs can control their activation and function through various pathways. MiR-432-5p, secreted by CAFs, promotes chemoresistance in prostate cancer by targeting CHAC1 to prevent ferroptosis (an iron-dependent cell death pathway) [ 116 ]. Similarly, miR-92a, also secreted by CAFs, aids breast cancer invasion and metastasis by modulating G3BP2 [ 117 ]. Furthermore, miRNAs contribute to tumor resistance by targeting specific proteins. MiR-152-3p enhances radiotherapies resistance in cervical cancer by targeting KLF15 [ 118 ]. MiR-196a confers cisplatin resistance to head and neck squamous cell carcinoma by targeting CDKN1B and ING5 [ 119 ].

The regulatory function of miRNAs in the TME offers a theoretical foundation for developing new therapeutic approaches. Current applications of miRNAs in cancer therapies focus on three main areas: restoring the expression of tumor suppressor miRNAs, inhibiting oncogenic miRNAs, and using miRNAs as drug delivery vehicles. For instance, enhancing the expression of tumor suppressor miRNAs, like miR-34a, which targets multiple oncogenes including Notch1 and Bcl-2, can inhibit osteosarcoma progression [ 120 ]. Similarly, suppressing the activity of oncogenic miRNAs represents another key therapeutic strategy. MiR-21, overexpressed in various cancers, can be targeted with antisense oligonucleotides (ASOs) or miRNA inhibitors to reduce its levels and curb tumor growth [ 121 ]. Studies show miR-21 also advances hepatocellular carcinoma by targeting PTEN and PDCD4 [ 122 ]. Progress has also been noted in using miRNAs for drug delivery. Plant-derived exosomes have enhanced miRNA bioavailability and delivery in tumors [ 123 ]. Additionally, engineered exosomes have been shown to specifically reprogram CAFs, improving pancreatic cancer treatments [ 124 ]. These findings highlight the significant potential of miRNAs as drug delivery carriers.

LncRNAs

LncRNAs have emerged as significant regulators in various cancers over recent years. These molecules influence fundamental biological processes, including cell proliferation, apoptosis, and migration. Additionally, lncRNAs play a crucial role in the TME. This review focuses on the regulatory mechanisms of lncRNAs within this environment and their effects on immune cells, metabolic reprogramming, and therapies. It also explores the potential of lncRNAs as biomarkers and therapeutic targets.

LncRNAs play a crucial role in the tumor immune microenvironment. They influence tumor development and treatment effectiveness by modulating immune cell function, infiltration, and the expression of immune checkpoint molecules [ 125 ]. For instance, lncRNA EGFR, highly expressed in hepatocellular carcinoma, promotes the differentiation of CD4 + T cells into Tregs. This process inhibits the cytotoxic T cells’ ability to kill tumor cells, allowing tumors to evade immune surveillance [ 126 ]. LncRNA TUG1 acts as a sponge for miR-141 and miR-340, regulating the expression of PD-L1 and CD47, respectively. It also interacts with YBX1 to enhance the transcription of PD-L1 and CD47, promoting tumor immune escape [ 127 ]. Research indicates that lncRNA H19 correlates positively with the infiltration levels of various immune cells, such as CD4 + T cells, CD8 + T cells, B cells, dendritic cells, neutrophils, and macrophages. It is also associated with multiple immune markers in thyroid cancer [ 128 ]. Moreover, lncRNA TRPM2-AS is vital in shaping the tumor immune microenvironment in endometrial cancer. Its overexpression in these cancer cells triggers the polarization and angiogenesis of M2 macrophages via the secretion of SPP1-rich exosomes [ 129 ]. These insights highlight the intricate roles of lncRNAs in the tumor im-mune microenvironment and offer new angles for developing lncRNA-targeted interventions.

LncRNAs significantly impact tumor cell metabolism, influencing tumor progression. They affect multiple metabolic pathways, including glycolysis, amino acid metabolism, and fatty acid metabolism. In glycolysis, lncRNAs modulate key enzyme activities, altering energy production in tumor cells. For instance, lncRNA HULC boosts glycolytic rates in hepatocellular carcinoma by activating the LDHA/PKM2 pathway, enhancing cancer cell proliferation [ 130 ]. SNHG6, identified in colorectal cancer, intensifies glycolysis through the hnRNPA1/PKM signaling axis, increasing cancer cell numbers and invasion capabilities, as well as distant metastasis [ 131 ]. TAMs deliver myeloid-specific lncRNA HISLA via extracellular vesicles (EVs), boosting aerobic glycolysis and apoptosis resistance in breast cancer cells [ 132 ]. Beyond glycolysis, lncRNAs regulate amino acid metabolism; lncRNA XLOC_006390 promotes pancreatic carcinogenesis and glutamate metabolism by stabilizing c-Myc [ 133 ]. Fatty acid metabolism is another area where lncRNAs exert influence. The m6A-modified lncRNA POU6F2-AS1 reprograms fatty acid metabolism and accelerates colorectal cancer growth by upregulating FASN [ 134 ]. Overall, lncRNAs shape tumor biology by disrupting various metabolic pathways, highlighting their importance in cancer research for understanding disease mechanisms and identifying therapeutic targets.

LncRNAs serve various roles in TME therapies, acting as prognostic markers, immunotherapies indicators, and potential therapeutic targets. They offer crucial insights into patient survival and reactions to specific treatments. High levels of lncRNA CRNDE correlate with cisplatin resistance in gastric cancer [ 135 ], while elevated lncRNA HOTAIR expression in small-cell lung cancer links to faster disease progression and worse outcomes [ 136 ]. LncRNAs are also valuable for predicting responses to immune check inhibitors (ICIs) therapies [ 137 ]. Research indicates that MHC-1 serves as a significant biomarker in ICIs [ 138 ], and lncRNA LIMIT enhances MHC-I expression and tumor immunogenicity, boosting checkpoint therapies effectiveness [ 139 ]. This highlights the potential of targeting specific lncRNAs to improve ICI performance. Additionally, lncRNAs represent a promising direct therapeutic target. Manipulating their expression or blocking their functions can help manage or reverse tumor growth. For instance, silencing lncRNA MALAT1, which shows abnormal activity in cutaneous T-cell lymphoma, can slow tumor progression [ 140 ]. Thus, developing therapies aimed at key lncRNAs like MALAT1 could become a critical focus in advancing cancer treatment strategies.

The role of lncRNAs in the TME is gaining increasing attention. These molecules influence immune cell function, metabolic reprogramming, and therapeutic response via various mechanisms. Future research should delve deeper into the precise actions of lncRNAs, aiming to identify new biomarkers and therapeutic strategies. This work could offer novel insights for advancing precision cancer therapies.

CircRNAs

In recent years, ncRNAs, particularly circRNAs, have garnered significant attention for their roles in cancer development, progression, and immunotherapies. These molecules are crucial in various biological processes such as regulating gene expression and protein function [ 141 ]. CircRNAs exhibit high stability, conservation, and tissue specificity, which makes them promising candidates as biomarkers and therapeutic targets [ 142 ].

CircRNAs can regulate gene expression by functioning as miRNA sponges. For instance, circSHKBP1 promotes gastric cancer progression and inhibits HSP90 degradation by modulating the miR-582-3p/HUR/VEGF axis [ 143 ]. Additionally, circSMARCC1 disrupts the interaction between prostate cancer cells and tumor-associated macrophages via the miR-1322/CCL20/CCR6 pathway, thus fostering tumor progression [ 144 ]. Moreover, circFTO moves from M2-type macrophages to non-small cell lung cancer (NSCLC) cells through small extracellular vesicles (sEVs), enhancing NSCLC malignancy by adjusting the miR-148a-3p/PDK4 axis [ 145 ]. These findings indicate that circRNAs can serve as miRNA sponges to influence key signaling pathways, impacting cell behavior within the TME. Furthermore, circRNAs regulate tumor progression through protein interactions in the TME. CircBBS9, for example, modulates the tumor immune microenvironment by directly binding to the IFIT3 protein, influencing the early diagnosis of lung adenocarcinoma [ 146 ]. CircRNAs also impact the TME by altering immune cell function. CircATP8A1 advances gastric cancer progression by inducing macrophage M2 polarization through the miR-1-3p/STAT6 axis [ 147 ]. Similarly, circPOLQ promotes macrophage M2 polarization by activating the IL-10/STAT3 axis, affecting the immunotherapies effectiveness in colorectal cancer [ 148 ]. CircNDUFB2 restrains NSCLC progression by destabilizing IGF2BPs and boosting anti-tumor immunity [ 149 ]. Additionally, circRNAs play a crucial role in tumor metabolic reprogramming. CircMBOAT2 facilitates intrahepatic cholangiocarcinoma progression and lipid metabolic reprogramming by stabilizing PTBP1 to assist FASN mRNA cytoplasmic export [ 150 ]. CircSIPA1L3 elevates lactate export and glucose uptake by increasing SLC16A1 levels through enhanced interaction with IGF2BP3 or by serving as a sponge for miR-665 to stabilize RAB11A mRNA, leading to intensified glycolytic metabolism [ 151 ].

CircRNAs play significant roles in tumorigenesis, development, and immune regulation due to their unique structural and functional characteristics. They offer new insights into cancer therapies. Recent research indicates that circRNAs influence tumor cell behavior by modulating gene expression and signaling pathways. Additionally, they can either enhance or suppress immune responses by altering the function of immune cells, thereby impacting the efficacy of immunotherapies. For instance, circRNF216 influences colorectal cancer progression by controlling tumor metastasis and CD8 + T cell infiltration via the miR-576-5p/ZC3H12C axis. The intricate mechanisms governing how circRNAs interact with immune cells within the TME have been elucidated, offering a theoretical foundation for the creation of novel immunotherapeutic approaches [ 152 ]. CircRNAs have garnered significant attention for their involvement in ICI therapies. Research has demonstrated that circRNAs can alter the outcomes of ICIs by adjusting the expression of immune checkpoint molecules like PD-1 and PD-L1, and by affecting T cell function. An example is circBART2.2, which is overexpressed in nasopharyngeal carcinoma, leading to increased PD-L1 levels and diminished T-cell-mediated cytotoxicity, resulting in reduced T-cell infiltration and apoptosis [ 153 ]. Moreover, circRNAs can boost the anti-tumor immune response by activating dendritic cells, enhancing antigenic cross-presentation, and stimulating CD4 + and CD8 + T cells [ 154 ]. These discoveries suggest that circRNAs hold promise in cancer immunotherapies. CircRNA-based vaccine complexes have been shown to elicit robust antigen-specific T cell responses and powerful antitumor effects [ 155 ]. Furthermore, the potential of circRNAs as tumor diagnostic and prognostic markers is becoming more evident, with their stable expression unaffected by splicing variability or cellular conditions making them suitable as potential biomarkers [ 156 ].

In summary, circRNAs significantly influence the regulation of the TME. Future research will uncover more detailed mechanisms of circRNAs, offering a solid theoretical foundation and technical support for developing new circRNA-based approaches to tumor diagnosis and therapies. Table 1 ; Fig. 4 comprehensively summarize the diverse roles of various ncRNAs within the TME.

Table 1 Non-coding RNAs play multiple biological functions in the TME ncRNAs Cancer Types Mechanisms Functions References MiR-1247-3p Bladder Cancer Targets FOXO1 Promotes angiogenesis, accelerates tumor growth [ 107 ] MiR-146a Ovarian Cancer Targets immune-suppressive neutrophils Increases CD8 + T cell infiltration, inhibits tumor growth [ 111 ] MiR-432-5p Prostate Cancer Secreted by CAFs, targets CHAC1 Inhibits ferroptosis, promotes chemotherapy resistance [ 116 ] MiR-152-3p Cervical Cancer Targets KLF15 Enhances radioresistance [ 118 ] lncRNA TUG1 Various Cancers Regulates PD-L1 and CD47 expression Promotes tumor immune evasion [ 127 ] lncRNA H19 Thyroid Cancer Associated with immune cell infiltration Enhances immune cell infiltration, accelerates tumor progression [ 128 ] lncRNA HULC Hepatocellular Carcinoma Activates LDHA/PKM2 pathway Promotes glycolysis and cell proliferation [ 130 ] lncRNA MALAT1 Cutaneous T-cell Lymphoma Abnormal activity Accelerates tumor progression [ 140 ] circSHKBP1 Gastric Cancer Acts as a miRNA sponge, regulates miR-582-3p/HUR/VEGF Promotes tumor progression [ 143 ] circSMARCC1 Prostate Cancer Regulates TAMs via miR-1322/CCL20/CCR6 Promotes tumor progression [ 144 ] circATP8A1 Gastric Cancer Induces M2 polarization, regulates miR-1-3p/STAT6 axis Promotes tumor progression [ 147 ] circPOLQ Colorectal Cancer Activates IL-10/STAT3 axis to regulate M2 polarization Affects immunotherapy response [ 148 ] circNDUFB2 Non-small Cell Lung Cancer Inhibits tumor progression by stabilizing IGF2BP Enhances anti-tumor immunity [ 149 ]

Fig. 4 Non-coding RNAs play multiple biological functions in the TME. The image was drawn via Figdraw with permission

Recent advances and challenges in clinical translation of different NcRNAs

Recent advances in MiRNAs in the TME

MiRNAs, as crucial regulators of gene expression, play a pivotal role in various diseases, particularly in cancer development. Recent years have seen significant advancements in the clinical translational research of miRNAs, encompassing their application as diagnostic markers, therapeutic targets, and drug delivery systems [ 157 ]. Notably, miRNA-based PROTACs have been developed to target the oncogenic protein Lin28 for breast cancer treatment. By effectively degrading Lin28A via a ubiquitin-proteasome-dependent pathway, this approach increases the levels of mature let-7 family miRNAs, which subsequently inhibit cancer cell proliferation, migration, and enhance chemotherapies sensitivity [ 158 ]. Using heterobifunctional PROTAC probes to degrade BET proteins can enhance the expression of MICA (a ligand for the NKG2D receptor) in multiple myeloma cells, thereby more effectively activating natural killer cells. The specific mechanism involves upregulating certain miRNAs, such as miR-125b-5p, which downregulates the cMYC/miR-125b-5p target gene IRF4, leading to increased MICA expression [ 159 ]. Additionally, in endometrial cancer, the upregulation of hsa-mir-200a-b and hsa-mir-429 is associated with decreased expression of genes like PTCH1, CCND2, and ALDH1A1. These miRNAs may also be linked to PROTACs [ 160 ], suggesting their potential role in modulating these pathways and contributing to the broader implications of miRNA-based PROTACs therapies across different cancer types. Additionally, MNA enzyme-based nanomachines can cleave heat shock protein (HSP) mRNA by reducing oncogene miR-NA-21, leading to enhanced expression of the tumor suppressor gene PTEN and pancreatic tumor suppression under laser irradiation [ 161 ]. Moreover, miR-28-based combination therapies have shown promise in treating aggressive B-cell lymphomas by restoring DNA replication control [ 162 ]. Despite these notable achievements, numerous challenges still exist in both basic research and clinical translation of miRNAs.

Clinical translational challenges of MiRNAs

MiRNA bioavailability and off-target effects are two critical considerations when utilizing miRNAs as therapeutic tools. Firstly, regarding miRNA bioavailability, studies have shown that synthetic miRNA mimics such as Dicer substrates (e.g., Dsi155 and Dmi155) need to possess appropriate structural features to ensure they are efficiently taken up by cells and processed into mature miRNAs. Specifically, Dmi155, which has a bulge structure similar to the endogenous pre-miR-155, is more effectively loaded onto Argonaute proteins compared to perfectly matched Dsi155, highlighting the importance of structure for miRNA bioavailability [ 163 ].

On the other hand, off-target effects represent a significant challenge in using miRNA therapies. Because miRNAs typically act through imperfect complementary pairing with multiple mRNA targets, they may inadvertently regulate the expression of unintended genes, leading to undesirable biological consequences. For instance, while miR-155 can enhance the immune-stimulating capability of tumor-associated dendritic cells (DCs), inappropriate design or delivery methods might cause miR-155 not only to affect the intended targets but also to interfere with other important signaling pathways or cellular processes, thereby producing side effects [ 163 ]. Moreover, certain chemical modifications, although capable of increasing the stability and pharmacokinetic properties of miRNAs, may alter their specificity, thus exacerbating the risk of off-target effects [ 164 ].

The delivery of miRNA poses a significant barrier to its clinical use. Unprotected miRNAs are prone to rapid degradation by nucleases in the body, leading to a short half-life and potential off-target effects. Efficient delivery systems must be developed to protect miRNAs and ensure they reach their intended targets safely and effectively [ 165 , 166 ]. Nanotechnology offers solutions, with multifunctional elastin-like peptide nanocarriers and bioswitchable miRNA mimic delivery systems showing promise in enhancing miRNA delivery and stability [ 167 – 169 ]. Nanocarriers, such as the aforementioned elastin-like peptide nanocarriers, exhibit higher stability and longer circulation time in the blood due to their small size, surface functionalizability, and capability for targeted delivery. However, the design and production of nanocarriers are typically more complex and come with relatively higher costs [ 170 ]. On the other hand, liposomes, serving as carriers, possess good biocompatibility and ease of modification, effectively encapsulating miRNAs and facilitating cellular uptake. Yet, they may suffer from potential toxic side effects [ 171 ]. Therefore, selecting the appropriate carrier technology requires a comprehensive consideration of various factors within the specific application context.

The intricate role of miRNAs in biology complicates efforts to understand their functions. A single miRNA can influence the expression of many genes, while a single gene can be controlled by several miRNAs. This complexity hinders the identification of specific miRNA functions and their roles in disease mechanisms [ 172 – 174 ]. Despite encouraging outcomes from preclinical studies, miRNA therapies have encountered challenges during clinical trials. For instance, methods involving oligonucleotides and gene therapy to regulate miRNAs are particularly difficult for conditions like neurological disorders and have not gained clinical approval [ 175 ]. The delivery system may induce toxic side effects due to the significant impact of carrier technology selection on biodistribution, targeting specificity, and immunogenicity [ 176 ]. The functional complexity of miRNAs increases the difficulty in identifying their precise roles and mechanisms in disease, as a single miRNA can regulate multiple genes, and individual genes can be influenced by several different miRNAs [ 176 ]. Additionally, the safety risks of directly intervening in gene expression networks include off-target effects caused by unintended gene silencing or activation, as well as potential unknown consequences of long-term use [ 176 ]. Future research should concentrate on overcoming these obstacles to advance the clinical application of miRNA therapies.

In summary, despite facing challenges like delivery issues, complex functionality, and safety concerns, the obstacles to clinical translation of miRNAs are being progressively addressed (Table 2 ). Advances in nanotechnology and high-throughput screening are aiding this process [ 177 ]. Ongoing improvements in delivery systems, coupled with deeper insights into miRNA mechanisms, suggest that miRNAs could emerge as a promising therapeutic approach, offering new strategies for treating major diseases, including cancer [ 178 ].

Table 2 Recent advances and challenges in clinical translation of MiRNAs Applications Descriptions References Diagnostic markers Use of miRNAs for diagnosing various diseases, particularly cancer. [ 157 ] Therapeutic targets miRNA-based PROTACs targeting oncogenic protein Lin28 for breast cancer treatment. [ 158 ] Drug delivery systems Enhancing miRNA delivery and stability using nanotechnology and multifunctional nanocarriers. [ 167 – 169 ] Combination therapies miR-28-based combination therapies for treating aggressive B-cell lymphomas. [ 162 ] Challenges Delivery issues, complex functionality, safety concerns, and off-target effects. [ 165 , 166 , 172 – 176 ] Nanotechnology solutions Development of elastin-like peptide nanocarriers and bioswitchable miRNA mimic delivery systems. [ 167 – 169 ] Liposomes Good biocompatibility and ease of modification, but potential toxic side effects. [ 171 ] High-throughput screening Identifying miRNAs with therapeutic potential and understanding their mechanisms. [ 177 ] Future research Advancing delivery systems and deeper insights into miRNA mechanisms to overcome current obstacles. [ 178 ]

Recent advances in LncRNAs in the TME

In recent years, lncRNAs have become a focal point in research, with their roles in gene expression, cellular differentiation, and diseases like cancer being widely acknowledged [ 179 ]. Notably, clinical translational research on lncRNAs has seen significant advancements. Research indicates that lncRNAs are crucial in cancer initiation, progression, and metastasis. For instance, lncRNAs such as MALAT1, HOTAIR, and PVT1 exhibit abnormal behavior in various cancers and correlate with patient outcomes [ 180 – 182 ]. MALAT1 exhibits pro-oncogenic functions in multiple cancer types by modulating angiogenesis in endothelial cells and promoting tumor cell migration and metastasis [ 180 ]. HOTAIR contributes to cancer progression by reshaping chromatin architecture to suppress tumor suppressor genes and by regulating signaling pathways that enhance tumor invasion and metastasis [ 181 ]. Additionally, PVT1 promotes cancer cell proliferation and survival by directly targeting multiple miRNAs and activating associated signaling pathways [ 182 ]. Targeted therapies against these lncRNAs, including RNA inter-ference (RNAi), antisense oligonucleotides, and small molecule inhibitors, have shown promising outcomes in preclinical studies [ 183 – 185 ]. These findings establish a strong basis for utilizing lncRNAs in cancer diagnosis and treatment.

Clinical translational challenges of LncRNAs

The clinical translation of lncRNAs faces numerous challenges. The tissue-specificity and variable expression levels of lncRNAs complicate their use as biomarkers or therapeutic targets [ 186 ]. Efficiently delivering lncRNAs to target cells while preserving their activity remains a critical issue [ 187 ]. For instance, in gastric cancer lymph node metastasis, the micro-protein pep-AKR1C2, encoded by exosomal lncAKR1C2, enhances fatty acid oxidation and ATP production by modulating YAP phosphorylation, thus boosting the migration of lymphatic vessel endothelial cells. Yet, inhibiting pep-AKR1C2 to prevent lymph node metastasis is challenging [ 188 ]. The intricate mechanisms of lncRNAs involve extensive molecular networks and regulatory pathways, necessitating deeper fundamental research to elucidate their functions [ 189 – 191 ]. Additionally, the stability and specificity of lncRNAs impact their suitability as therapeutic targets; developing technologies for specific recognition and degradation of target lncRNAs requires further refinement [ 192 , 193 ]. Addressing these challenges demands interdisciplinary collaboration and technological advancements. Researchers are exploring various strategies to improve the clinical utility of lncRNAs. High-throughput screening and gene editing tools like Cas13d/CasRx help identify lncRNAs with therapeutic potential and uncover their mechanisms [ 194 ]. Advances in delivery systems, including nanoparticles, liposomes, and viral vectors, offer new ways to precisely deliver lncRNAs [ 195 , 196 ]. Furthermore, siRNAs and ASOs targeting specific lncRNAs have shown promise in treating certain conditions, with good safety and efficacy profiles [ 197 ]. Increasingly, lncRNA studies are advancing to clinical trials, highlighting their potential in treating cancers, cardiovascular diseases, and neuro-degenerative disorders [ 198 , 199 ].

In conclusion, as our understanding of the biological functions of lncRNAs deepens and technology advances, the clinical application of lncRNAs will present new opportunities for precision medicine (Table 3 ).

Table 3 Recent advances and challenges in clinical translation of LncRNAs Applications Descriptions References Cancer diagnostics and treatment LncRNAs like MALAT1, HOTAIR, and PVT1 exhibit abnormal behavior in cancers and correlate with patient outcomes. [ 180 – 182 ] Targeted therapies RNA interference (RNAi), antisense oligonucleotides, and small molecule inhibitors showing promising outcomes. [ 183 – 185 ] Challenges Tissue-specificity, variable expression levels, and efficient delivery issues. [ 186 , 187 ] Molecular mechanisms Extensive molecular networks and regulatory pathways complicate understanding of lncRNA functions. [ 189 – 191 ] Stability and specificity Developing technologies for specific recognition and degradation of target lncRNAs. [ 192 , 193 ] High-throughput screening and gene editing Using Cas13d/CasRx for identifying therapeutic potential and uncovering mechanisms. [ 194 ] Advanced delivery systems Using nanoparticles, liposomes, and viral vectors for precise lncRNA delivery. [ 195 , 196 ] Clinical trials Increasingly advancing to clinical trials for treating cancers, cardiovascular diseases, and neurodegenerative disorders. [ 198 , 199 ]

Recent advances in LncRNAs in the TME

The circRNA is a distinctive ncRNA molecule that has garnered significant attention in tumor biology. This interest stems from its closed-loop structure, which confers high stability and tissue specificity. Initially, circRNAs were considered the result of splicing errors or by-products of RNA transcription, deemed incapable of encoding proteins [ 200 ]. Advances in bioinformatics, RNA sequencing, and genome sequencing have since unveiled the mechanisms behind circRNA production and their cellular functions [ 201 ]. Due to their widespread presence, conservation, stability, and distinct expression patterns in tumor patients compared to healthy individuals, circRNAs hold great preclinical promise for diagnosing and treating various tumors [ 202 ]. Early studies have highlighted the involvement of specific circRNAs in tumor progression and immunotherapies, suggesting new targets for cancer immunotherapies [ 203 – 205 ].

Clinical translational challenges of circrnas

Despite the significant potential of circRNAs for clinical applications, several scientific challenges must be overcome before their full promise can be realized. Only 10–20% of circRNAs are conserved between humans and mice, limiting the translational relevance of findings from animal models to human patients [ 206 ]. Current technologies also face limitations, such as inefficient circRNA synthesis and high costs for enzymes and reagents, which complicate the development of circRNA biomarkers and cancer immunotherapies [ 207 ]. Additionally, many circRNA biomarkers remain underdeveloped, and existing assessments often rely on comparisons with adjacent or normal tissues, rather than considering the dynamic changes in the tumor microenvironment, including immune cell secretion, inflammatory factors, and cytokines [ 208 ]. Research indicates that multiple factors, such as gene mutations, chromosomal copy number alterations, aberrant methylation, and post-transcriptional modifications, collectively drive the initiation and progression of CRC, all of which can lead to abnormal gene expression. Specifically, within the dynamics of the TME, changes like immune suppression and tumor-promoting induction play crucial roles [ 209 ]. Additionally, mesenchymal stem cells (MSCs), as a vital component of the dynamic TME, have been utilized to investigate the function of Circ_0004303 [ 210 ]. Therefore, when conducting ncRNA studies, it is essential to consider the dynamic changes in the TME. This broader perspective will enhance our understanding of circRNA mechanisms and explore their potential as diagnostic and prognostic biomarkers, as well as therapeutic targets or vehicles.

To address these challenges, researchers are investigating targeted therapies that leverage the distinctive properties of circRNAs. For instance, circRNA-targeting vectors encapsulated in lipid nanoparticles (LNPs) can adjust circRNA expression in tumors, minimizing side effects on healthy cells and enhancing both patient recovery rates and quality of life [ 211 ]. Researchers have developed and refined immune-deficient mice, enabling the transplantation of human genes, cells, tissues, or organs into these models. This process allows the reactions observed in the mice to offer more dependable insights for therapeutic approaches. Acting as a crucial link between clinical applications and basic research, humanized mice are becoming an increasingly vital tool in the preclinical assessment of cancer treatments [ 212 ]. Additionally, the study demonstrated the potential of using human liver organoids derived and cultured from HBV-infected patients as a research platform. These organoids are not only capable of supporting HBV infection and replication but can also be utilized for drug screening, such as the effective inhibition of HBV replication by Tenofovir. This approach overcomes the limitations inherent in traditional animal models and cell line models, including the lack of relevance to human physiology and differences in gene expression profiles due to tumor origins [ 213 ]. CircRNAs, being reliable indicators of immunotherapeutic response, also hold promise for use in tumor vaccine development to boost anti-tumor immune reactions [ 214 ].

Combining circRNAs with current clinical treatments, such as PD1/PD-L1 immune checkpoint inhibitors, can more effectively activate the host’s immune system to combat tumor immune evasion, offering a novel approach to cancer immunotherapies [ 215 ]. Studies have shown that CircRHBDD1 promotes immune evasion through the IGF2BP2/PD-L1 signaling pathway and serves as a nano-therapeutic target in gastric cancer [ 216 ]. Although translating circRNAs into clinical applications presents numerous obstacles, their significant potential in cancer diagnosis and therapies underscores their importance for future research endeavors (Table 4 ).

Table 4 Recent advances and challenges in clinical translation of circrnas Applications Descriptions References Tumor biology Closed-loop structure confers high stability and tissue specificity, making circRNAs promising for cancer diagnostics and therapeutics. [ 202 , 204 , 205 ] Scientific challenges Limited conservation between humans and mice, inefficient synthesis, high costs, and underdeveloped biomarkers. [ 206 – 208 ] Tumor microenvironment (TME) Dynamic changes in TME, including immune cell secretion and inflammatory factors, complicate circRNA study. [ 209 , 210 ] Targeted therapies CircRNA-targeting vectors encapsulated in lipid nanoparticles to adjust expression in tumors. [ 211 ] Humanized mice and liver organoids Used for more reliable therapeutic insights and drug screening. [ 212 , 213 ] Tumor vaccine development CircRNAs as reliable indicators of immunotherapeutic response and potential in tumor vaccines. [ 214 ] Combination therapies Combining circRNAs with PD1/PD-L1 inhibitors for effective tumor immune evasion combat. [ 215 , 216 ]

Clinical applications of NcRNAs in the TME

Non-coding RNA-based therapeutics: promising candidates and ongoing trials

Therapies utilizing ncRNAs are showing great promise in clinical treatments (Table 5 ). For example, a study [ 217 ] explored how the lncRNA-miRNA-mRNA network responds to Lactobacillus acidophilus consumption in rectal cancer patients. Results indicated that consuming probiotics boosted the expression of tumor-suppressing miRNAs and lncRNAs while reducing oncogenic ones. Significant correlations were observed between certain components, such as miR-133b with IGF1 and miR-21 with SMAD4. The findings suggest that L. acidophilus can enhance the lncRNA-miRNA-mRNA network’s expression, offering new therapeutic approaches. Additionally, MRX34, which is a liposome-encapsulated miR-34a mimic, has undergone Phase I trials for advanced solid tumors [ 218 ], demonstrating manageable toxicity and some efficacy. Meanwhile, an ongoing Phase I trial is assessing TUG1 antisense oligonucleotide (TUG1ASO) for recurrent glioblastoma, using a drug delivery system capable of crossing the blood-brain barrier [ 219 ].

CircRNAs, known for their stability, are emerging as valuable biomarkers. One study [ 220 ] identified several circRNAs (like hsa_circ_0041150 and hsa_circ_0036683) downregulated in hepatocellular carcinoma (HCC). These circRNAs’ low expression correlates with poorer patient survival rates. Particularly, hsa_circ_0036683 stands out as a key prognostic marker. Moreover, a locked nucleic acid (LNA) inhibitor targeting miR-221 (LNA-i-miR-221) was developed and tested in preclinical models, showing antitumor activity and favorable safety profiles in animals. In human trials, it demonstrated good safety, did not reach maximum tolerated dose (MTD), and showed signs of efficacy in some patients. A dose of 5 mg/kg is recommended for further studies [ 221 ].

Table 5 Clinical applications of NcRNAs in the TME Category Study/Therapy Clinical Phase Subjects Key Findings Citation lncRNA-miRNA-mRNA Lactobacillus acidophilus effect on rectal cancer patients Randomized Clinical Trial 117 subjects (107 cancer, 10 non-cancer) Probiotics increased tumor-suppressive RNAs [ 217 ] miRNA MRX34 (miR-34a mimic) Phase I Clinical Trial Advanced solid tumors Manageable toxicity, some clinical activity [ 218 ] miRNA TUG1 antisense oligonucleotide (TUG1ASO) Phase I Clinical Trial Recurrent glioblastoma Ongoing, penetrates blood-brain barrier [ 219 ] circRNA Multiple circRNAs (e.g., hsa_circ_0041150, hsa_circ_0001020) High-throughput sequencing Hepatocellular carcinoma Downregulated circRNAs linked to poor survival [ 220 ] miRNA Inhibitor 13-mer LNA inhibitor of miR-221 (LNA-i-miR-221) Phase I Dose-escalation Xenografts in mice, rats, monkeys Antitumor activity, stable disease, partial responses [ 221 ]

The roles of NcRNAs in clinical oncology: potential and challenges

Non-coding RNA has emerged as a promising player in the field of clinical oncology, offering unique advantages in early cancer diagnosis, prognosis evaluation, and personalized treatment strategies [ 222 ]. Certain ncRNAs, such as miRNAs and lncRNAs, exhibit abnormal expression patterns at the early stages of tumor development, making them potential biomarkers for detecting malignancies before traditional methods might identify them [ 223 ]. These molecules are involved in regulating key biological processes including cell proliferation, apoptosis, and differentiation, and their expression profiles can provide valuable insights into disease progression and patient outcomes. For example, specific miRNA signatures have been associated with survival rates and treatment responses in various cancers, enabling clinicians to identify high-risk patients and tailor therapeutic approaches accordingly [ 224 , 225 ]. Moreover, ncRNAs offer new avenues for targeted therapy by influencing drug sensitivity and resistance, thereby enhancing the precision and effectiveness of cancer treatments [ 27 ].

Despite their promise, the application of ncRNAs in clinical oncology faces several challenges that must be addressed before they can be widely adopted. One major limitation is the issue of specificity—while some ncRNAs show altered expression in certain cancers, many are also present in normal tissues or other disease states, which can compromise their reliability as standalone biomarkers [ 176 , 226 ]. Additionally, current technologies for detecting and quantifying ncRNAs are still evolving, with limitations in sensitivity, reproducibility, and standardization across different laboratories and platforms. The complexity of ncRNA regulatory mechanisms further complicates their use, as these molecules often function within intricate networks involving multiple layers of gene regulation [ 226 ]. Translating these findings from bench to bedside also requires extensive validation through large-scale clinical trials, regulatory approval, and integration into existing diagnostic and therapeutic frameworks [ 121 , 227 ]. Therefore, while ncRNAs hold significant potential to advance cancer care, overcoming these technical and biological hurdles remains critical to fully realizing their clinical utility.

From discovery to clinic: a roadmap for translating NcRNA research into therapeutic applications

To successfully translate research findings on ncRNAs from the laboratory into clinical applications, the following technological roadmap can be followed:

Discovery phase

Utilize high-throughput sequencing technologies to identify novel ncRNAs. Validate their functional roles using in vitro cell models.

Biomarker development phase

Screen for ncRNAs with potential diagnostic or prognostic value and validate them using patient-derived samples.

Therapeutic strategy design phase

Develop therapeutic agents such as siRNAs or ASOs targeting specific ncRNAs. Design delivery systems—such as nanoparticles or liposomes—to enhance therapeutic efficacy and minimize side effects.

Screening and gene editing phase

Employ CRISPR/Cas13d-based platforms for large-scale ncRNA screening. Investigate the molecular mechanisms and disease-related functions of selected ncRNAs.

Animal model testing phase

Evaluate the safety and efficacy of the developed therapies in preclinical animal models. Optimize dosing regimens and administration routes based on experimental outcomes.

Clinical trial phase

Proceed through successive phases of clinical trials:

Phase I: Focus on safety and tolerability in a small group of subjects. Phase II: Assess preliminary efficacy and determine optimal dosing. Phase III: Conduct large-scale trials comparing the new therapy to existing standard treatments.

Commercialization preparation phase

Prepare and submit a New Drug Application (NDA) to regulatory authorities. Develop strategies for manufacturing, distribution, and marketing.

Post-marketing surveillance phase

Monitor the long-term safety and effectiveness of the approved product in real-world settings. Continuously refine the product and associated technologies based on post-market data.

Prospect

As research on ncRNAs advances, their crucial role in cancer development is becoming increasingly evident. Due to their high stability in body fluids, these ncRNAs also hold promise as key biomarkers for the early diagnosis and screening of cancer [ 228 ]. The advent of single-cell RNA sequencing (scRNA-seq) technology has enabled the profiling of the transcriptome at the cellular level, allowing researchers to uncover gene expression patterns in different cell types within human cancers [ 229 ]. The INs-seq technology, which integrates scRNA-seq with the detection of intracellular protein activity, has demonstrated its capability in unveiling the immunosuppressive role of TREM2 within the tumor microenvironment [ 230 ]. Specifically, by employing the MetaCell approach, a computational method designed for clustering single-cell transcriptomic data and identifying cell subpopulations with high precision, it is possible to identify specific cell subpopulations and further dissect gene expression patterns within these subgroups [ 231 ]. Moreover, when conducting ncRNA analysis using high-throughput sequencing data, examining marker genes of different cell types (such as Ear2, Cx3cr1, Arg1, etc.) allows researchers to more precisely understand the functions of cell-type-specific ncRNAs [ 230 ]. Additionally, a base-editing sensor library based on the CRISPR-Cas9 system has been utilized for efficient engineering and functional analysis of cancer-associated single nucleotide variants, offering new perspectives and technical approaches for ncRNA research [ 232 , 233 ]. These technologies and methodologies not only enhance our understanding of the biological functions of ncRNAs but also provide potential avenues for developing novel therapeutic strategies.

One of the key future research directions involves constructing a more comprehensive ncRNA interaction network. This will aid researchers in uncovering the associations between ncRNAs and cancer, enabling the development of computational models for cancer prediction [ 234 ]. Additionally, the study of ncRNA biomarkers has emerged as a focal point in the scientific community. Gathering experimentally validated data on the differential analysis of ncRNA biomarkers and their associated genes at the single-cell level can offer critical insights. Such insights are essential for deepening our understanding of the roles these biomarkers play in human cancers [ 235 ].

As technology progresses, a key challenge for the future lies in translating fundamental research findings into practical clinical applications. For instance, the development of ncRNA-based liquid biopsy technology enables early-stage cancer detection, which can improve patient survival rates [ 236 ]. Additionally, the role of ncRNAs in tumor immunotherapies is attracting increasing attention. Research indicates that ncRNAs can boost the efficacy of tumor immunotherapies by modulating immune cell functions [ 237 ]. Consequently, future research should delve deeper into the precise mechanisms by which ncRNAs influence tumor immunotherapies, providing a solid theoretical foundation for innovative treatment strategies. Moreover, there is a need to develop more efficient delivery methods to ensure that ncRNA-based drugs can accurately target cells and deliver their therapeutic benefits [ 238 , 239 ].

Conclusions

Non-coding RNAs, such as miRNAs, lncRNAs, and circRNAs, do not encode proteins but are vital for gene expression regulation, intercellular communication, and the TME formation. This review examines the structural characteristics of miRNAs, lncRNAs and circRNAs, along with their roles in the TME. Research shows that these ncRNAs contribute to tumorigenesis and progression through intricate mechanisms, promoting tumor growth and metastasis while influencing the host immune system’s capacity to detect and combat tumors.

The paper also highlights recent advancements in the clinical application of miRNAs, lncRNAs, and circRNAs. The clinical translation of non-coding RNAs faces numerous challenges, such as off-target effects during RNAi and the scalability issues associated with nanoparticle delivery systems. Off-target effects can lead to unintended gene silencing, posing potential safety risks. Nanoparticles, although promising for efficient and safe in vivo delivery, encounter difficulties in maintaining consistency and stability during large-scale production, along with cost and manufacturing feasibility concerns. Additionally, challenges such as poor tissue specificity, immune activation, and insufficient long-term safety data further hinder the broad clinical application and development of non-coding RNA-based therapies.

Considering the significant impact of ncRNAs on tumor biology and their potential as therapeutic targets or biomarkers, future research should focus on elucidating the specific functions of different ncRNA types and advancing the development of next-generation anticancer therapies based on ncRNAs. This could pave the way for personalized cancer treatments, offering more precise and effective interventions. As research progresses, it is anticipated that novel ncRNA-based therapies will soon become a reality, greatly enhancing the prognosis of cancer patients.

Electronic supplementary material

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Supplementary Material 1

Publisher’s note

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Acknowledgements

Not applicable.

Author contributions

DM drafted this review and designed the figures; BH completed the data collection and provided editorial assistance; HH and YZ gave some valuable suggestions; JZ and YS provided the design and revision of the manuscript. All authors made substantial, direct and intellectual contribution to the review. All authors read and approved the final manuscript.

Funding

Funding This work was supported by the Science and Technology Department Public Welfare Project of Zhejiang Province (grant no. LGF22H160032) and the Medical and Health Science and Technology Project of Zhejiang Province (grant no. 2022RC107 and 2023KY501).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Abbreviations

non-coding RNAs

microRNAs

long non-coding RNAs

circular RNAs

Tumor microenvironment

Vascular endothelial growth factor

Tissue inhibitor of metalloproteinases

Histone deacetylase 2

Specificity protein 1

Cisplatin resistance

Head and neck squamous cell carcinoma

Osteosarcoma

Small nucleolar RNA host gene 7

Glioblastoma multiforme

Extracellular vesicles

Pancreatic ductal adenocarcinoma

Natural killer

Transforming growth factor beta

Extracellular signal-regulated kinase 1/2

Matrix metalloproteinases

Protein kinase AMP-activated catalytic subunit alpha

AMP-activated protein kinase alpha

Serine/threonine kinase 11

Fragile X mental retardation protein

Cell cycle and apoptosis regulator protein 1

Hepatocellular carcinoma

CKLF-like MARVEL transmembrane domain containing 6

Programmed death-ligand 1

Colorectal cancer

Immune checkpoint inhibitors

single-cell RNA sequencing

RNA interference

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