Long non-coding RNAs in the exosomal network: dual roles and clinical implications in cancer

ABSTRACT

Exosomes are a type of extracellular vesicles with a diameter of 30–150 nm, formed within multivesicular bodies of late endosomes, and released into the extracellular environment before being taken up by recipient cells. Exosomes transfer bioactive molecules, such as proteins and various RNAs, between cells and thereby influence recipient cell behavior. Among these molecules, long non-coding RNAs (lncRNAs) are not only selectively packaged into exosomes but have also been reported to participate in exosome biogenesis and secretion. Furthermore, they can contribute to cancer development by regulating gene expression through epigenetic mechanisms such as miRNA sponging, protein interactions, and methylation. These mechanisms appear to drive tumorigenesis by altering the tumor microenvironment, including macrophage polarization, immune evasion and suppression, angiogenesis, and lymphangiogenesis-mediated metastasis. In addition, exosomal lncRNAs can be readily detected in serum, highlighting their potential as biomarkers for liquid biopsy-based diagnosis. Finally, exosomal lncRNAs have been reported to contribute to drug resistance in various cancers. Therefore, therapeutic strategies targeting exosomal lncRNAs are expected to improve clinical outcomes in cancer patients.

1. Introduction

Extracellular vesicles (EVs) are heterogeneous populations of nano- to micro-sized vesicles secreted by nearly all cell types studied to date, ranging from prokaryotes to eukaryotes (Willms et al. 2016). Since their discovery, EVs have been detected in almost all biological fluids (Thery et al. 2018). Due to their critical roles, including potential applications as biomarkers for liquid biopsy and as therapeutic agents, EVs have attracted unprecedented attention (de Jong et al. 2019; Hoshino et al. 2020). Based on the MISEV 2023 guidelines, EVs are categorized primarily by their physical characteristics and biogenesis. Small EVs (<200 nm in diameter), often referred to as exosomes, originate from the endosomal pathway. Medium/large EVs include microvesicles (100–1000 nm), which bud directly from the plasma membrane, and apoptotic bodies (50–5000 nm), which are shed during programmed cell death (Anand et al. 2019; Welsh et al. 2024). Among these, exosomes are the most extensively characterized. Exosomes are 30-150 nm in diameter and originate from endocytic compartments, maturing within multivesicular bodies (MVBs) of the late endosome (Fevrier and Raposo 2004; Nawaz et al. 2014). Upon maturation, MVBs fuse with the plasma membrane to release exosomes into the extracellular space, after which they can be taken up by recipient cells.

This review focuses on exosomes, the most studied type of EV. Unlike cells, exosomes contain little to no 18S and 28S ribosomal RNA (Eldh et al. 2010; Lasser et al. 2011), and their RNA composition differs substantially from that of the donor cell cytoplasm (Ekstrom et al. 2012; Montecalvo et al. 2012). These differences suggest that RNA incorporation into exosomes is not a random event during exosome biogenesis but is instead governed by tightly regulated sorting and packaging mechanisms that generate a distinct RNA subset specific to exosomes (Janas et al. 2015; Villarroya-Beltri et al. 2014). However, the precise mechanisms by which extracellular small RNAs are selectively sorted and packaged into exosomes remain largely unknown. EVs transfer bioactive molecules, including proteins and various RNA species, between cells, thereby influencing recipient cell behavior (Pitt et al. 2016). Among EV cargo, RNA molecules have attracted considerable interest due to their potential to modulate gene expression in recipient cells (Prieto-Vila et al. 2021). The RNA cargo within EVs is biologically active and exerts profound effects on recipient cell functions (Eldh et al. 2010). For example, microRNAs (miRNAs) delivered via EVs can bind complementary sequences in target mRNAs, suppress target expression and induce gene silencing (Ong et al. 2014). This process can modulate a broad spectrum of cellular functions, including proliferation, differentiation, and apoptosis (Ding et al. 2021b; He et al. 2020; Raimondo et al. 2020).

Accumulating evidence indicates that most multicellular organisms maintain exosome-mediated communication via the intercellular exchange of non-coding RNAs (ncRNAs). Valadi et al. were the first to report the presence of both mRNAs and miRNAs in exosomes (Valadi et al. 2007). Subsequent studies have identified various ncRNA species within exosomes (Qu et al. 2016; Shao et al. 2019). More than 98% of the human genome is transcribed into ncRNAs, which participate in diverse physiological and pathophysiological processes (Slack and Chinnaiyan 2019; Yoon et al. 2025). NcRNAs play essential roles in gene expression regulation, epigenetic modulation, RNA splicing and translation, protein degradation, and trafficking. Notably, tumor-derived exosomal ncRNAs are abundant, highly stable, and act as messengers in intercellular communication (Hong et al. 2009; Spinelli et al. 2018). Among various ncRNAs, long non-coding RNAs (lncRNAs) have recently emerged as particularly important regulators in cancer (Roh et al. 2023a; Seo et al. 2021). LncRNAs, a group of ncRNAs longer than 200 nucleotides, contribute to tumorigenesis by altering the expression of numerous downstream cancer-related genes (Im et al. 2025; Jang et al. 2023; Roh et al. 2023b). Additionally, lncRNAs induce various therapeutic resistances in different cancers by altering mechanisms such as metabolism, cell proliferation, and apoptosis (Chae et al. 2021; Roh et al. 2022). Specific RNA-binding proteins (RBPs), such as heterogeneous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1) and ALG-2-interacting protein X (ALIX), facilitate the selective packaging of lncRNAs into exosomes for intercellular transport (Fabbiano et al. 2020). Encapsulation within exosomes enables long-distance transport of lncRNAs between cells, tissues, and organs, and protects them from degradation by extracellular RNases (Moonmuang et al. 2021). By combining the long-range signaling capabilities of exosomes with the regulatory potential of lncRNAs, exosomal lncRNAs play a central role in modulating the tumor microenvironment. They regulate gene expression, signaling pathways, and drug efflux, thereby promoting the spread of chemoresistance and functioning as key regulators within tumorigenic networks (Mirzaei et al. 2022). Exosomal lncRNAs contribute to cancer progression by enhancing angiogenesis, invasion, and metastasis, as well as promoting immune escape and chemoresistance (Cheng et al. 2024; Wang et al. 2024b). In the context of tumor–microenvironment interactions, exosomal lncRNAs exert critical functions and exhibit strong potential as diagnostic markers and therapeutic targets (Xu et al. 2022; Zhang et al. 2021). They can act as competing endogenous RNAs (ceRNAs) and miRNA sponges to regulate target gene expression, or they may bind directly to target proteins to influence ubiquitination and phosphorylation, thereby modulating protein expression and activity (Chae et al. 2024; Jang et al. 2025). Nevertheless, the mechanisms by which exosomal lncRNAs mediate tumor metastasis remain incompletely understood, owing to the diversity of intracellular and intercellular targets involved.

Recently, increasing attention has been directed toward understanding how exosomal lncRNAs contribute to tumorigenesis. However, most previous studies have primarily focused on their roles as cargo molecules delivered to recipient cells, without fully addressing their additional function as regulators of exosome biogenesis and secretion. In this review, we highlight the dual roles of exosomal lncRNAs, first as key regulators of exosome biogenesis and release; and second, as cargos that reprogram the tumor microenvironment (TME) and promote tumor progression. By integrating these two perspectives, we provide a comprehensive overview of their molecular mechanisms across cancer types and discuss how they collectively drive tumor progression, therapeutic resistance, and TME remodeling. This approach underscores the clinical potential of exosomal lncRNAs as biomarkers and therapeutic targets, while also providing new insights into their central position within the exosomal communication network.

2. Molecular roles of lncRNAs in the exosomal pathway

Exosomes are increasingly recognized as critical mediators of intercellular communication, and lncRNAs contribute to this process in multiple ways (Abdelgawad et al. 2025). Importantly, the RNA composition of exosomes does not merely mirror the donor cell transcriptome, but rather reflects the outcome of selective incorporation via regulated sorting mechanisms (Statello et al. 2018). This incorporation is influenced by RNA-binding proteins (RBPs), post-transcriptional modifications, and intrinsic structural or sequence features of lncRNAs (Qiu et al. 2021). Beyond their role as cargo, lncRNAs also regulate exosome biogenesis and secretion, often through ceRNA network-mediated modulation of key proteins such as Rab GTPases and SNARE complex components (Dai et al. 2021; Salmena et al. 2011).

2.1. LncRNAs as exosomal cargo

In cells, most RNAs are present in the form of ribonucleoprotein (RNP) complexes, with RBPs functioning as essential regulators of RNA post-transcriptional processing, intracellular transport, subcellular localization, stability, and degradation (Curtis and Jeffery 2021) (Figure 1). Certain RBPs recognize specific sequences or structural motifs, thereby directing the selective loading of lncRNAs into exosomes (Wang and Zhang 2024a). Among these, hnRNPA2B1 has been identified as a pivotal mediator of exosomal lncRNA packaging and is consistently detected within exosomal fractions (Shirani et al. 2025). For instance, the GGAG/CCCU motif located at the 5′ terminus of lncRNA ARSR is indispensable for hnRNPA2B1 binding, and disruption of this motif impairs the interaction, resulting in markedly reduced lncRNA ARSR levels within exosomes (Qu et al. 2016). Comparably, lncRNA AGAP2-AS1 and lncRNA LNMAT2 strictly depend on direct interaction with hnRNPA2B1 (Chen et al. 2020; Zheng et al. 2019). In lncRNA LNMAT2, the GGAG motif and a stem-loop structure within nucleotides 1930–1960 are critical determinants for recognition. Another RBP, Y-box binding protein 1 (YBX1), participates in the sorting of lncRNAs into exosomes (Qiu et al. 2021). For example, the 252–272 nt region of lncRNA AC073352.1 directly associates with YBX1, thereby stabilizing YBX1 protein levels; silencing YBX1 significantly decreases lncRNA AC073352.1 abundance in exosomes (Kong et al. 2021).

Figure 1.

The Schematic illustrates how RNA-binding proteins and post-transcriptional modifications mediate the selective sorting of lncRNAs into exosomes. hnRNPA2B1 recognizes conserved motifs in ARSR (renal cancer), AGAP2-AS1 (glioma), and LNMAT2 (bladder cancer), while AC073352.1 (breast cancer) directly binds YBX1, stabilizing the protein and promoting its enrichment in exosomes. Additionally, m⁶A methylation enhances the stability of A1BG-AS1 (prostate cancer), and m⁵C methylation of MALAT1 (multiple myeloma) promotes its interaction with YBX1, thereby facilitating efficient exosomal loading. SUMOylation of hnRNPA1 further enables the selective recognition of ELNAT1, ensuring its efficient incorporation into exosomes.

Post-transcriptional modifications of lncRNAs can alter their structural stability and binding affinity to RBPs, thereby influencing their selective sorting into exosomes. For instance, N⁶-methyladenosine (m⁶A) modification plays an important role. Zinc finger CCCH-type containing 13-mediated m⁶A methylation of lncRNA A1BG-AS1 enhances its stability and promotes its enrichment in exosomes (Yang et al. 2024b). In addition, NOP2/Sun RNA methyltransferase 2 (NSUN2)-mediated 5-methylcytosine (m⁵C) modification of lncRNA MALAT1 facilitates its interaction with YBX1, thereby promoting its exosomal transport (Yu et al. 2024). LncRNA ELNAT1 is selectively loaded into exosomes through ubiquitin carrier protein 9 (UBC9)-mediated SUMOylation of hnRNPA1, with the stem-loop structure spanning nucleotides 610–680 nt being critical for recognition (Chen et al. 2021).

Exosomal lncRNAs are, on average, shorter than lncRNAs that are less abundant in exosomes (1993 nt vs. 3938 nt) and exhibit a higher exon density relative to their length (3.2 vs. 2.8 exons per kilobase). These features, which are also observed in exosomal mRNAs, are thought to enhance RNA stability and sorting efficiency (O'Grady et al. 2022). In addition, secondary structures such as stem-loops play an important role in mediating RBP binding, thereby facilitating selective incorporation into exosomes (Qiu et al. 2021).

2.2. LncRNAs as exosome controllers

Rab proteins are small GTPases that play essential roles in vesicle trafficking and membrane docking, acting as key regulators of MVB transport and exosome release (Sexton et al. 2019) (Figure 2). Rab11a, a critical regulator of endosomal recycling, promotes exosome secretion (Savina et al. 2005). In hepatocellular carcinoma (HCC), lncRNA HULC functions as a sponge for miR-372-3p to upregulate Rab11a expression, thereby increasing exosome secretion (Cao et al. 2019). Rab27a and Rab27b are essential Rab GTPases that regulate distinct steps in the exosome secretion pathway, facilitating MVB docking at the plasma membrane and subsequent exosome release (Ostrowski et al. 2010). Rab27a is involved in exosome docking and the reorganization of the subcortical actin cytoskeleton, whereas Rab27b controls the transport of exosomes to the plasma membrane (van Niel et al. 2018). In lung adenocarcinoma (LUAD), LINCRNA01703 directly binds to Rab27a and synaptotagmin-like 1 (SYTL1) to promote the assembly of the Rab27a/SYTL1/CD81⁺ complex, thereby enhancing the secretion of CD81⁺ exosomes and suppressing metastasis (Huang et al. 2023). LINC01703 expression is significantly reduced in metastatic LUAD, and its overexpression strengthens the Rab27a/SYTL1/CD81⁺ interaction. In addition, LINC00511 regulates the expression and localization of Rab27b, thereby promoting the colocalization of vesicle associated membrane protein 7 (VAMP7) and synaptosome associated protein 23 (SNAP23), which in turn promotes exosome secretion and invadopodia formation in HCC cells (Peng et al. 2021). Notably, LINC00511 overexpression markedly increases VAMP7-SNAP23 colocalization, thereby activating MVB-plasma membrane fusion and facilitating exosome release. Rab35 is a GTPase that promotes exosome secretion by regulating the docking and tethering of MVBs to the plasma membrane (Hsu et al. 2010). The lncRNA HOTAIR regulates the expression and subcellular localization of Rab35, thereby facilitating the transport and docking of MVBs to the plasma membrane, as well as promoting the colocalization of vesicle associated membrane protein 3 (VAMP3) and SNAP23, which in turn drives SNARE complex assembly and exosome release (Yang et al. 2019). In addition, lncRNA HOTAIR enhances SNARE complex activity by inducing SNAP23 phosphorylation via the mTOR signaling pathway. Rab5b functions as an upstream regulator of the endosomal sorting complex required for transport (ESCRT) pathway and is critical for MVB formation and the early stages of exosome biogenesis (Colombo et al. 2014; van Niel et al. 2018). In colorectal cancer (CRC), lncRNA APC1 directly binds to Rab5b mRNA, reducing its stability and thereby suppressing exosome production and attenuating tumorigenic potential (Wang et al. 2019). Rab7 generally mediates the fusion of late endosomes with lysosomes, leading to MVB degradation and a consequent reduction in exosome secretion (Bucci et al. 2000). However, the lncRNA PVT1 regulates the expression and localization of Rab7, thereby promoting MVB-plasma membrane docking and fusion, ultimately enhancing exosome release (Sun et al. 2020). LncRNA PVT1 upregulates Rab7 and concomitantly increases the expression of the v-SNARE proteins YKT6 and VAMP3, with a notable induction of YKT6 palmitoylation that activates the MVB-plasma membrane fusion step. These effects are markedly diminished upon Rab7 inhibition, indicating that Rab7 can be functionally repurposed by lncRNA-mediated regulation rather than serving solely as a degradation pathway factor.

Figure 2.

The Schematic illustrates how lncRNAs regulate exosome secretion by modulating multivesicular body transport and Rab GTPase-dependent pathways. Representative lncRNAs, including APC1 (colorectal cancer, CRC), HULC (hepatocellular carcinoma, HCC), LINC01703 (lung adenocarcinoma, LUAD), LINC00511 (oligodendroglia), HOTAIR (HCC), and PVT1 (pancreatic cancer), regulate Rab11a, Rab27a/b, Rab35, Rab5b, and Rab7, respectively thereby promoting multivesicular body transport, vesicle docking, and SNARE complex activation. In addition, lncRNAs such as ZNFX1-AS1 (bladder cancer), XIST (renal cell carcinoma), TRPM2-AS (ovarian cancer), LINC01116 (melanoma), WDFY3-AS2 (ovarian cancer), SOX21-AS1 (LUAD), and LINC00483 (CRC) modulate the expression of membrane-associated proteins, including SDC1, SDC2, SDC4, and TSPAN8, respectively linking exosome biogenesis and secretion to tumor progression.

In addition to Rab family proteins, membrane proteins such as the syndecan and tetraspanin families are also known to be involved in exosome biogenesis and secretion. Although direct experimental evidence showing that lncRNAs mediate exosome secretion through these proteins is currently lacking, several studies have reported that lncRNA-driven regulation of their expression can influence malignant phenotypes in various cancers. Syndecans are cell surface proteoglycans involved in cell adhesion, migration, and tumorigenesis, and may also contribute to exosome-mediated intercellular communication (Baietti et al. 2012). For example, lncRNA ZNFX1-AS1 promotes bladder cancer progression by sponging miR-193a-3p to upregulate syndecan 1 (SDC1) (Wu et al. 2020). Similarly, in renal cell carcinoma (RCC), lncRNA XIST suppresses miR-302c, thereby increasing SDC1 expression and enhancing cell proliferation while inhibiting apoptosis (Zhang et al. 2017). In addition, lncRNA TRPM2-AS promotes ovarian cancer progression by sponging miR-138-5p to release syndecan 3 (SDC3) mRNA, and lncRNA WDFY3-AS2, overexpressed in ovarian cancer, by sponging miR-139-5p to upregulate syndecan 4 (SDC4), whose overexpression reverses these inhibitory effects (Ding et al. 2021c; Wu et al. 2021). Furthermore, LINC01116, overexpressed in melanoma, facilitates tumor progression by sponging miR-3612 to increase SDC3 expression (Wang et al. 2022b). Tetraspanins are major components and canonical markers of exosomes, functioning to regulate diverse molecular and cellular events at the plasma membrane. Among them, tetraspanin 8 (TSPAN8) regulates exosome biogenesis (Yang et al. 2024a). In LUAD, lncRNA SOX21-AS1 interacts with the transcription factor GATA binding protein 6 (GATA6) to upregulate TSPAN8 expression, thereby promoting colony formation, proliferation, and invasion (Xu et al. 2020). Similarly, in CRC, LINC00483 acts as a sponge for miR-601, increasing TSPAN8 expression, which in turn facilitates tumor progression (Liu et al. 2025). These findings indicate that syndecans and tetraspanins may serve as critical regulatory nodes in lncRNA-mediated cancer biology. Further investigations are needed to elucidate how these axes are directly linked to the regulation of exosome biogenesis and secretion. Such insights could open new avenues for the development of exosome-based strategies for cancer diagnosis and therapy.

3. Exosomal lncRNAs in the formation of tumor microenvironment

The TME, composed of tumor cells, immune cells, stromal cells, diverse signaling molecules, and an abundant extracellular matrix (ECM), constitutes a heterogeneous collection formed by tumor cells themselves (Jia et al. 2022). The TME is critical in promoting tumor growth, immune suppression, angiogenesis, and metastasis, and cancer cells remodel this environment to their advantage by releasing exosomal lncRNAs (Pathania and Challagundla 2021). Recent studies have revealed that exosomal lncRNAs are transferred to non-malignant recipient cells, where they precisely modulate phenotypes and functions, thereby contributing to the reprogramming of the TME by inducing immunosuppressive conditions, angiogenesis, lymphangiogenesis, and pre-metastatic niche formation.

3.1. Reprogramming tumor-associated macrophages regulated by exosomal lncRNAs

Tumor-associated macrophages (TAMs), one of the most abundant immune cell types in the TME, exhibit high plasticity and can be polarized into tumor-suppressive M1 or tumor-promoting M2 phenotypes (Gao et al. 2022; Myers et al. 2019). Among them, M2-polarized TAMs remodel the extracellular matrix, secrete anti-inflammatory cytokines, and stimulate angiogenesis, thereby establishing an immunosuppressive niche that facilitates tumor progression (Han et al. 2021; Martinez et al. 2008). Exosomal lncRNAs critically contribute to this process by reprogramming macrophages toward an M2-like state, ultimately supporting tumor growth and metastasis. In oral squamous cell carcinoma-derived cancer stem cells, lncRNA UCA1 is packaged into small EVs, and delivered to macrophages, where it sponges miR-134 to upregulate laminin subunit gamma 2 expression and to activate the PI3K/AKT signaling pathway (Wu et al. 2022). The activated pathway promotes M2 macrophage polarization, which in turn fosters an immunosuppressive TME that ultimately facilitates tumor growth. In non-small cell lung cancer (NSCLC), exosomal lncRNA PCAT6 acts in macrophages to sponge miR-326, upregulate KLF transcription factor 1, and induce M2 polarization, consequently enhancing NSCLC cell survival, migration, epithelial–mesenchymal transition (EMT), and metastasis (Chen et al. 2022b). In HCC, exosomal lncRNA SLC16A1-AS1 enhances lactate transporter activity and c-Raf/ERK signaling in macrophages, thereby driving M2 polarization (Hu et al. 2024). These M2 macrophages secrete interleukin-6, which upregulates methyltransferase-like 3 in HCC cells and stabilizes lncRNA SLC16A1-AS1, establishing a positive feedback loop that promotes tumor proliferation and glycolysis. Similarly, in laryngeal squamous cell carcinoma (LSCC), exosomal lncRNA HOTAIR activates PI3K/AKT signaling and suppresses phosphatase and tensin homolog (PTEN) expression in macrophage, thereby promoting M2 polarization, which ultimately stimulates tumor cell proliferation, migration, and EMT, and enhancing tumor progression (Wang et al. 2022a). In addition to its immunomodulatory function, lncRNA HOTAIR regulates exosome secretion by controlling Rab35 localization and SNARE complex assembly as detailed in Section 2.2 (Yang et al. 2019), indicating its involvement in both exosome biogenesis and the modulation of the TME. In colon cancer, exosomal lncRNA XIST is enriched in tumor-derived vesicles and transferred to macrophages, where it sponges miR-17-5p to upregulate platelet derived growth factor receptor alpha (PDGFRA) expression (Gao et al. 2024). The activated PDGFRA subsequently triggers AKT, ERK, and STAT3/6 pathways, thereby promoting M2 polarization of macrophages. These M2-like macrophages further enhance colon cancer cell proliferation, migration, and invasion, reinforcing an immunosuppressive TME. Interestingly, experimental evidence demonstrates that lncRNA XIST regulates SDC1 expression (Zhang et al. 2017). These findings together suggest that lncRNA XIST may play dual roles in exosome-associated processes and in modulation of the TME. Exosomal lncRNA ARSR from RCC cells also activates STAT3 signaling in macrophages, thereby promoting M2 polarization and tumor progression (Zhang et al. 2022). Although M2 polarization is the predominant outcome, some exosomal lncRNAs exert the opposite effect. In esophageal cancer, exosomal lncRNA LOC441178 is transferred to macrophages, where it suppresses tumor-promoting M2 polarization, associated with decreased phospho-STAT6 levels, thereby reducing invasion, migration, and EMT of esophageal cancer cells and attenuating tumor growth (Chen et al. 2022a).

3.2. Modulation of immune escape mechanisms by exosomal lncRNAs

In addition to reprogramming macrophage polarization, exosomal lncRNAs critically contribute to the establishment of immune escape mechanisms within the TME. These molecules regulate immune checkpoint signaling, such as the programmed cell death 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) axis, and suppress the cytotoxic activity of effector lymphocyates, including CD8⁺ T cells and natural killer (NK) cells (Huang et al. 2021; Mohamed et al. 2023). Through these processes, exosomal lncRNAs enable tumor cells to evade immune surveillance and promote resistance to immunotherapy. Exosomal lncRNA HOXC13-AS in LSCC sponges miR-485-5p to upregulate insulin like growth factor 2 mRNA binding protein 2, leading to increased PD-L1 expression and immune escape from CD4⁺ and CD8⁺ T cells (He et al. 2024a). Similarly, TAMs mediate the transfer of lncRNA RIME (also known as LINC02096) to esophageal squamous cell carcinoma cells via exosomes (Liu et al. 2023b). LncRNA RIME binds to mixed lineage leukaemia protein 1, leading to increased trimethylation levels of histone H3 at lysine 4 and subsequent upregulation of PD-L1 and indoleamine 2,3-dioxygenase 1. As a result, resistance to CD8⁺ T cell-mediated cytotoxicity is enhanced, consequently strengthening tumor immune evasion and immunotherapy resistance. Tumor-released exosomal LINC01214 in melanoma sponges miR-4492 in CD8⁺ T cells, increasing protein phosphatase 1 regulatory inhibitor subunit 11 expression and suppressing antitumor activity, ultimately promoting resistance to anti-PD-1 therapy (Ding et al. 2025). In CRC, exosomal lncRNA KCNQ1OT1, originating from tumor cells, sequesters miR-30a-5p, upregulating ubiquitin specific peptidase 22, which stabilizes PD-L1 by inhibiting its ubiquitination, thereby reducing CD8⁺ T cell-mediated killing and promoting immune evasion (Xian et al. 2021). LncRNA NEAT1, encapsulated in exosomes originating from M2-polarized tumor-associated macrophages, is delivered to HCC cells, where it induces the transcription factor KLF5 and facilitates increased Galectin-3 expression (Yuan et al. 2025). Galectin-3 suppresses the antitumor immune response of CD8⁺ T cells, thus enhancing immune evasion in HCC. In glioblastoma (GBM), exosomal lncRNA AGAP2-AS1 released by tumor cells is delivered to myeloid-derived suppressor cells, where it inhibits miR-486-3p, activates TGF-β1 signaling, and suppresses cytotoxic T cell activity, facilitating tumor growth and metastasis (Tian et al. 2024). Exosomal lncRNA PWAR6 from cancer-associated fibroblasts (CAFs) activates nuclear factor erythroid 2-related factor 2 signaling in CRC cells, increasing glutamine uptake (Fang et al. 2024). As a result, glutamine deprivation occurs in NK cells, suppresses cytotoxicity, thereby promoting immune evasion mechanisms. Likewise, exosomal lncRNA SNHG10 upregulates inhibin subunit beta C and activates TGF-β signaling in NK cells, thereby suppressing their cytotoxic function and promoting tumor progression (Huang et al. 2021).

3.3. Promotion of angiogenesis and lymphangiogenesis by exosomal lncRNAs

Angiogenesis and lymphangiogenesis are essential processes in the TME, supplying nutrients and oxygen, supporting stromal remodeling, and creating conduits for malignant cell dissemination (Zhao et al. 2024). Sustained formation of new blood and lymphatic vessels provides tumors with the means to expand locally while simultaneously establishing routes that enable metastatic spread. Exosomal lncRNAs contribute to these processes by modulating endothelial cell activity, inducing EMT, and fostering pre-metastatic niche formation, thereby linking vascular remodeling in the TME to systemic dissemination. In NSCLC, LINC00511 has been identified as a representative example of dual functionality (Zhu et al. 2023b). As described in Section 2.2, it derepresses Rab27a by sponging miR-124-3p, leading to increased exosome secretion and concurrent activation of PI3K/AKT signaling, which drives proliferation, migration, invasion, and metastatic progression. This study provides direct evidence that a single lncRNA can regulate exosome biogenesis while also promoting vascular remodeling and metastatic behavior. Other lncRNAs further exemplify this multifunctional behavior. In osteosarcoma, bone marrow-derived exosomes transfer lncRNA PVT1 to tumor cells, where it stabilizes ERG and sponges miR-183-5p, enhancing proliferation and metastatic progression (Zhao et al. 2019). In colon cancer, circulating exosomal lncRNA PVT1 promotes angiogenesis and stemness through the PVT1/miR-152-3p/VEGFA axis (Lai et al. 2021). In laryngeal cancer, exosomal circPVT1, a circular RNA derived from the lncRNA PVT1, sponges miR-30c-5p to upregulate Rap1b, leading to activation of VEGFR2/PI3K/AKT signaling and inducing angiogenesis (Lyu et al. 2024). These findings collectively demonstrate that lncRNA PVT1 can function as an exosomal cargo driving angiogenesis and dissemination, and lncRNA PVT1 has also been implicated in promoting exosome release through Rab7-mediated pathways as described in Section 2.2, highlighting its multifaceted roles in tumor progression. In pancreatic ductal adenocarcinoma (PDAC), lncRNA HULC is induced by TGF-β and enriched in extracellular vesicles, where it promotes EMT and enhances the invasive capacity of recipient cells (Takahashi et al. 2020). Beyond this cargo-mediated effect, lncRNA HULC also promotes exosome release via the Rab11a pathway as described in Section 2.2, demonstrating its multifaceted involvement in exosome dynamics and tumor progression. In gallbladder cancer, exosomal lncRNA TRPM2-AS activates NOTCH1 signaling in endothelial cells, driving angiogenesis and metastasis (He et al. 2024b). Also, it sponges miR-497-5p to upregulate SPP1, which stimulates angiogenesis and promotes M2 macrophage polarization, resulting in bridged immune remodeling with vascular expansion in endometrial carcinoma (Ma et al. 2024). In PDAC, exosomal lncRNA SOX21-AS1 is delivered to endothelial cells, where it sponges miR-451a and elevates EREG, leading to enhanced angiogenesis and tumor progression (Yan et al. 2024). As previously noted, lncRNA TRPM2-AS regulates SDC3 expression, and lncRNA SOX21-AS1 controls TSPAN8 expression. These observations suggest that these lncRNAs participate in both exosome-related regulation and cargo-mediated remodeling of the TME.

Moreover, several other exosomal lncRNAs have been reported to act primarily as cargos that promote vascular remodeling and metastasis. LncRNA LNMAT2 in bladder cancer binds hnRNPA2B1 and recruits it to the prospero homeobox 1 (PROX1) promoter, increasing H3K4me3 levels and inducing PROX1 expression, thereby promoting lymphangiogenesis and lymph node metastasis (Chen et al. 2020). In gastric cancer, exosomal lncRNA AKR1C2 encodes a micropeptide (pep-AKR1C2) that suppresses Hippo-YAP signaling, induces carnitine palmitoyltransferase 1A (CPT1A) expression and fatty acid oxidation, and enhances lymphangiogenesis and lymph node dissemination (Zhu et al. 2023a). In breast cancer, lncRNA SNHG12 relieves PBRM1-mediated repression of MMP10, resulting in stimulating vascular endothelial proliferation and angiogenesis (Chen et al. 2024). In ovarian cancer, exosomal lncRNA ATB sponges miR-204-3p, thereby increasing TGFbR2 expression, and promoting endothelial activation, angiogenesis, and EMT (Yuan et al. 2022). LINC01356, derived from highly metastatic NSCLC cells, disrupts tight junction proteins in brain microvascular endothelial cells, increasing blood–brain barrier permeability and facilitating brain invasion (Geng et al. 2022). Additionally, exosomal lncRNA SOX2OT in NSCLCs sponges miR-194-5p to elevate Rac family small GTPase 1 (RAC1) expression and activate the TGF-β/pTHrP/RANKL pathway, leading to osteoclast activation, bone resorption, and bone metastasis (Ni et al. 2021). These studies expand the landscape of exosomal lncRNAs in vascular and metastatic niche remodeling, though their regulatory functions in exosome biogenesis remain largely unexplored.

Taken together, these findings indicate that exosomal lncRNAs orchestrate angiogenesis, lymphangiogenesis, and metastatic progression through diverse mechanisms. Some lncRNAs, such as LINC00511, PVT1, HULC, TRPM2-AS, and SOX21-AS1, exhibit multifunctional properties by influencing both exosome production and cargo-mediated signaling, whereas others primarily act as cargos that drive vascular and stromal remodeling. Particularly for lncRNAs with dual roles, most reported mechanisms have been observed in different cancer types, leaving it uncertain whether similar effects occur within the same tumor context. Therefore, further studies are needed to determine whether their dual functions in regulating exosome secretion and remodeling the TME operate in a cancer-type-specific manner or represent a generalizable phenomenon.

4. Exosomal lncRNAs as clinical biomarkers and therapeutic resistance mediators

The composition and expression changes of exosomal lncRNAs directly reflect patients’ clinical status, and accumulating evidence has demonstrated their potential utility across diverse cancer types for diagnosis, prognosis, monitoring, and prediction of therapeutic responses (Wang et al. 2020). For LUAD, lncRNA OIP5-AS1 was significantly upregulated in tumor tissues compared to adjacent normal tissues, and its elevated expression was also observed in the serum and serum-derived exosomes of LUAD patients (Ji et al. 2024). Notably, serum exosome-based receiver operating characteristic (ROC) analysis yielded an area under the ROC curve (AUC) of approximately 0.76-0.80, indicating their potential as auxiliary biomarkers for liquid biopsy-based diagnosis in LUAD. In HER2-positive breast cancer, serum exosomal lncRNA OIP5-AS1 levels were elevated in the trastuzumab nonresponsive group and achieved an AUC of 0.764 (sensitivity 59.26%, specificity 93.33%), suggesting its potential as a biomarker for the classification and prediction for trastuzumab resistance classification and prediction. (Yu et al. 2021). In the context of cervical cancer, serum exosomal lncRNA DLX6-AS1 was markedly increased compared to healthy controls and cervical intraepithelial neoplasia (CIN) (Ding et al. 2021a). Diagnostic accuracy analysis revealed that the distinction between cervical cancer and healthy controls achieved an AUC of 0.892 (sensitivity 78.1%, specificity 88.2%). In contrast, the discrimination between cervical cancer and CIN yielded an AUC of 0.831 (sensitivity 75.4%, specificity 71.8%). High expression of lncRNA DLX6-AS1 was correlated with lymph node metastasis, tumor differentiation grade, and stage according to the International Federation of Gynecology and Obstetrics. Its levels significantly decreased at 90 days after surgery or treatment, but rose again upon recurrence. Elevated lncRNA DLX6-AS1 was associated with poor prognosis in both overall survival (OS) and relapse-free survival, and multivariate Cox analysis identified it as an independent prognostic factor for OS. DLX6-AS1 was markedly upregulated in NSCLC tumor tissues, serum, and serum exosomes, and its silencing suppressed NSCLC cell proliferation and migration in vitro (Zhang et al. 2019a). Serum DLX6-AS1 levels were associated with advanced stage, lymph node metastasis, and poor differentiation, and considerably decreased following surgery, suggesting its tumor-derived nature. Exosomal DLX6-AS1 showed a pronounced increase in NSCLC patients compared with healthy controls, and previous studies have demonstrated that exosomal lncRNAs are more stable than their free circulating counterparts, thereby supporting their suitability as biomarkers. In addition, serum-based ROC analysis showed that lncRNA DLX6-AS1 achieved superior diagnostic performance (AUC = 0.806) compared with the conventional protein marker CYFRA21-1 (AUC = 0.600), highlighting its potential as a promising biomarker for early NSCLC diagnosis. For GBM, serum and exosomal HOTAIR levels were elevated compared to standard controls, yielding an AUC of 0.913 (sensitivity 86.1%, specificity 87.5%) for diagnosis (Tan et al. 2018). Paired tumor tissue-serum analyses from the same patients demonstrated a strong correlation (r ≈ 0.73) in lncRNA HOTAIR expression, which was detectable in exosomes. Post-surgical decreases in serum HOTAIR further support its potential as a liquid biopsy biomarker. In urothelial bladder cancer, lncRNA HOTAIR expression was also upregulated in tumor tissues and urinary exosomes compared with healthy controls, and it could be proposed as a noninvasive diagnostic and monitoring biomarker candidate (Berrondo et al. 2016). Representative examples of clinically relevant exosomal lncRNAs that function as diagnostic and prognostic biomarkers across different cancer types are summarized in Table 1.

Table 1.

The value of exosomal lncRNAs in the clinical management of cancer.

lncRNA	Cancer type	Liquid biopsy source	Value	Ref.
OIP5-AS1	Lung cancer	Serum	Cancer diagnosis	Ji et al. 2024
	Breast cancer	Serum	Treatment efficacy	Yu et al. 2021
DLX6-AS1	Cervical Cancer	Serum	Cancer diagnosis, Treatment efficacy, Prognosis evaluation	Ding et al. 2021a
	Lung cancer	Serum	Cancer diagnosis, Treatment efficacy	Zhang et al. 2019a
HOTAIR	Glioma	Serum	Cancer diagnosis, Treatment efficacy	Tan et al. 2018
	Bladder Cancer	Urine	Cancer diagnosis, Treatment efficacy	Berrondo et al. 2016

Exosomal lncRNAs can be delivered to recipient cells, modulating their responsiveness to therapy and thus facilitating drug resistance across diverse cancers (Yu et al. 2021). In-depth elucidation of these functions could contribute to the development of promising therapeutic targets. For instance, in trastuzumab-resistant HER2-positive breast cancer cells, exosomal LINC00969 is transferred to trastuzumab-sensitive HER2-positive breast cancer cells, where it binds to the RNA-binding protein HuR, enhancing HER2 mRNA stability and expression, and simultaneously promoting autophagy, thereby reinforcing cell survival and trastuzumab resistance (Liu et al. 2023a). Likewise, in docetaxel-resistant triple-negative breast cancer (TNBC), exosomal LINC00667 is delivered to TNBC cells, where it sponges and inhibits miR-200b-3p, leading to upregulation of BCL2, which reduces TNBC cell chemosensitivity to docetaxel (Li et al. 2022). Under hypoxic conditions, pancreatic stellate cells secrete exosomes that contain lncRNA UCA1 (Chi et al. 2021). These exosomes are transferred to pancreatic cancer cells, where lncRNA UCA1 binds directly to the enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) and enhances EZH2-mediated H3K27me3 levels at the suppressor of cytokine signaling 3 (SOCS3) promoter, thereby promoting epigenetic silencing of SOCS3 and malignant phenotypes, including gemcitabine resistance. In gastric cancer, M2 macrophage-derived exosomes deliver the lncRNA CRNDE to tumor cells via clathrin-mediated endocytosis, where CRNDE recruits NEDD4-1 to PTEN, promoting PTEN ubiquitination and thereby reducing PTEN protein levels, activating the PI3K/AKT pathway, and consequently, inducing cisplatin resistance in tumor cells (Xin et al. 2021). Using a recurrent, temozolomide-resistant GBM model, researchers found that exosomal lncRNA SBF2-AS1 is transferred to temozolomide-sensitive GBM cells, where it sponges miR-151a-3p in the cytoplasm, upregulates the DNA double-strand break (DSB) repair gene X-ray repair cross complementing 4 (XRCC4), reduces γ-H2AX levels, accelerates DNA damage repair, and suppresses temozolomide-induced apoptosis, thus promoting chemoresistance (Zhang et al. 2019b). In HCC, TGF-β enhances the expression of lncRNA LINC-ROR in tumor cells and promotes its secretion EVs, including exosomes (Takahashi et al. 2014). LINC-ROR delivered to tumor cells via these secreted EVs suppresses p53 activation and reduces apoptosis, leading to the induction of resistance to sorafenib. Furthermore, LINC-ROR enhances the stem-like properties of tumor-initiating cells, exacerbating overall therapeutic resistance. From CAFs in CRC, exosomal H19 is delivered to tumor cells, where it sponges miR-141 and activates the Wnt/β-catenin pathway, thereby inducing tumor stemness and oxaliplatin resistance (Ren et al. 2018). Finally, in small cell lung cancer, CAF-derived exosomal lncRNA MEG3 is transferred to tumor cells, where it suppresses miR-15a-5p, thereby upregulating cyclin E1 expression and increasing cisplatin resistance (Sun et al. 2022). The diverse molecular mechanisms by which exosomal lncRNAs mediate therapeutic resistance across multiple cancer types are schematically illustrated in Figure 3.

Figure 3.

The schematic illustrates how exosomal lncRNAs induce therapeutic resistance through diverse molecular mechanisms. Exosomal lncRNAs contribute to chemoresistance across multiple cancer types by stabilizing oncogenic mRNAs, sponging miRNAs, recruiting epigenetic modifiers, and suppressing tumor suppressor pathways.

Collectively, the expression alterations and functional roles of exosomal lncRNAs across various cancer types indicate that they reflect patients’ clinical status and play a crucial role in regulating therapeutic responsiveness and drug resistance. Accordingly, exosomal lncRNAs are regarded as a promising molecular class that can provide important clues not only for diagnosis, prognosis, and monitoring, but also for identifying novel therapeutic targets to overcome drug resistance.

5. Conclusion

Exosomal lncRNAs can be selectively packaged into exosomes through interactions with RBPs, post-transcriptional modifications, and unique structural motifs, and they regulate exosome biogenesis and secretion by modulating the expression of proteins in the Rab GTPase family and the SNARE complex. Once produced, these exosomes selectively load lncRNAs, which can subsequently remodel the tumor microenvironment and contribute to cancer development (Table 2). Exosomal lncRNAs induce macrophage polarization and promote cancer cell survival, migration, EMT, and metastasis. Other exosomal lncRNAs regulate immune cells, thereby contributing to tumorigenesis through mechanisms such as immune evasion and immunosuppression. In addition, specific exosomal lncRNAs promote angiogenesis, lymphangiogenesis, and metastasis, thereby facilitating tumor cell proliferation and growth. Multiple exosomal lncRNAs alter gene expression and remodel the tumor microenvironment through molecular mechanisms such as ceRNA networks via miRNA sponging, direct protein interactions, and methylation, ultimately driving cancer progression. These exosomal lncRNAs can be readily detected in serum, enabling their potential use as biomarkers for liquid biopsy-based diagnosis in various cancers. The detection of serum exosomal lncRNAs also allows for the assessment of drug resistance, supporting the development of personalized therapeutic strategies. Moreover, therapeutic approaches targeting these exosomal lncRNAs may increase drug sensitivity and improve clinical outcomes in cancer patients.

Table 2.

Representative lncRNAs and their roles in cancer progression.

lncRNA	Cancer type	Donor cell	Recipient cell	Role	Key molecular mechanism	Functional outcome	Ref.
HOTAIR	–	–	–	Biogenesis regulator	Rab35–VAMP3/SNAP23 axis	Increased exosome secretion	Yang et al. 2019
	LSCC	Tumor cell	Macrophage	Cargo	PI3K/AKT-PTEN axis	M2 polarization; EMT	Wang et al. 2022a
	GBM; Bladder cancer	Tumor cell	-	Biomarker	-	Liquid biopsy	Tan et al. 2018; Berrondo et al. 2016
PVT1	-	-	-	Biogenesis regulator	Rab7–YKT6/VAMP3 axis	Increased exosome secretion	Sun et al. 2020
	Osteosarcoma	Bone marrow stromal cell	Tumor cell	Cargo	miR-183-5p sponging; ERG stabilization	Proliferation; metastasis	Zhao et al. 2019
	CRC	Tumor cell	Tumor cell	Cargo	miR-152-3p/VEGFA axis	Stemness	Lai et al. 2021
circPVT1	Laryngeal cancer	Tumor cell	Endothelial cell	Cargo	miR-30c-5p/Rap1b axis; VEGFR2–PI3K/AKT signaling	Angiogenesis	Lyu et al. 2024
HULC	HCC	Tumor cell	-	Biogenesis regulator	miR-372-3p/Rab11a axis	Increased exosome secretion	Cao et al. 2019
	PDAC	Tumor cell	Tumor cell	Cargo	TGF-β–induced HULC; EMT-related signaling	EMT; invasion	Takahashi et al. 2020
LINC00511	-	-	-	Biogenesis regulator	Rab27b–VAMP7/SNAP23 axis	Exosome secretion; invadopodia formation	Peng et al. 2021
	NSCLC	Tumor cell	Tumor cell	Biogenesis regulator; cargo	miR-124-3p/Rab27a axis; PI3K/AKT signaling	Exosome secretion; metastasis	Zhu et al. 2023b
TRPM2-AS	Ovarian cancer	Tumor cell	-	-	miR-138-5p/SDC3 axis	Proliferation; tumor progression	Ding et al. 2021
	gallbladder cancer	Tumor cell	Endothelial cell	Cargo	NOTCH1 signaling	Angiogenesis; metastasis	He et al. (2024a)
	endometrial carcinoma	Tumor cell	Endothelial cell; macrophage	Cargo	miR-497-5p/SPP1 axis	Angiogenesis; M2 polarization	Ma et al. 2024
SOX21-AS1	LUAD	Tumor cell	-	-	GATA6–TSPAN8 transcriptional axis	Proliferation; invasion	Xu et al. 2020
	PDAC	Tumor cell	Endothelial cell	Cargo	miR-451a/EREG axis	Angiogenesis; tumor progression	Yan et al. 2024
LINC01703	LUAD	Tumor cell	-	Biogenesis regulator	Rab27a–SYTL1–CD81+ complex	Increased CD81+ exosome secretion; metastasis suppression	Huang et al. 2023
APC1	CRC	Tumor cell	-	Biogenesis suppressor	Rab5b mRNA destabilization	Reduced exosome biogenesis; tumor suppression	Wang et al. 2019
PCAT6	NSCLC	Tumor cell	Macrophage	Cargo	miR-326/KLF1 axis	M2 polarization; EMT; metastasis	Chen et al. 2022b
SLC16A1-AS1	HCC	Tumor cell	Macrophage	Cargo	Lactate transport–c-Raf/ERK signaling–mediated M2 polarization; IL-6–METTL3 positive feedback	M2 polarization; glycolysis; tumor proliferation	Hu et al. 2024
XIST	RCC	Tumor cell	Tumor cell	-	miR-302c/SDC1 axis	Proliferation; apoptosis inhibition	Zhang et al. 2017
	CRC	Tumor cell	Macrophage	Cargo	miR-17-5p/PDGFRA–AKT/ERK/STAT3/6 signaling	M2 polarization; immunosuppressive TME; tumor progression	Gao et al. 2024
PWAR6	CRC	CAF	Tumor cell	Cargo	NRF2 signaling–mediated glutamine uptake	NK cytotoxicity suppression; immune evasion	Fang et al. 2024
AGAP2-AS1	GBM	Tumor cell	myeloid-derived suppressor cell	Cargo	miR-486-3p sponging; TGF-β1 signaling	T cell suppression; tumor growth; metastasis	Tian et al. 2024
OIP5-AS1	LUAD	Tumor cell	-	Biomarker	-	Liquid biopsy	Ji et al. 2024
	HER2-positive breast cancer	Tumor cell	-	Biomarker	-	Trastuzumab resistance prediction	Yu et al. 2021
DLX6-AS1	Cervical cancer	Tumor cell	-	Biomarker	-	Diagnosis; prognosis; disease monitoring	Ding et al. 2021
	NSCLC	Tumor cell	-	Biomarker	-	Early diagnosis	Zhang et al. 2019a
SBF2-AS1	GBM	Tumor cell	Tumor cell	Cargo	miR-151a-3p/XRCC4 axis	DNA damage repair; temozolomide resistance	Zhang et al. 2019b
LINC-ROR	HCC	Tumor cell	Tumor cell	Cargo	p53 suppression; apoptosis inhibition	Stemness; sorafenib resistance	Takahashi et al. 2014
H19	CRC	CAF	Tumor cell	Cargo	miR-141 sponging; Wnt/β-catenin signaling	Stemness; oxaliplatin resistance	Ren et al. 2018

Disclosure statement

No potential conflict of interest was reported by the author(s).