Exosomal biomarkers and therapeutics in lung cancer: a narrative review on their role in early detection and targeted treatment

Introduction

Lung cancer remains a major global health burden, with consistently high incidence and mortality rates (1,2). Despite advances in targeted therapies and immunotherapy, the prognosis remains poor for most patients, primarily due to late-stage diagnosis and the emergence of resistance mechanisms (1,2). Conventional diagnostic approaches, including imaging and tissue biopsy, are limited in their ability to detect early-stage disease and to capture the dynamic nature of tumor evolution (3-5). Consequently, there is pressing need for novel, minimally invasive biomarkers that can improve early detection, predict treatment response and providing real-time insights into disease progression.

In recent years, the study of extracellular vesicles (EVs), particularly exosomes, has emerged as a promising platform for biomarker discovery and therapeutic delivery. Exosomes are nanoscale vesicles released by nearly all cell types and found in a wide range of biological fluids (6-9). Their lipid bilayer and selective cargo, which includes proteins, lipids and nucleic acids, reflect the physiological or pathological state of their cells of origin (8). In cancer, tumor-derived exosomes contribute to key hallmarks of malignancy, such as proliferation, immune evasion, angiogenesis, metastasis and therapeutic resistance (6,8,10-13). These characteristics position exosomes as attractive tools not only for diagnosis but also for therapeutic targeting—particularly relevant in lung cancer, where clinical needs remain largely unmet (14). We present this article in accordance with the Narrative Review reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-557/rc).

Methods

A comprehensive literature search was conducted between January 3 and April 30, 2025 using the following databases: PubMed/MEDLINE and Scopus. The search used free-text keywords related to lung cancer, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), exosomes, EVs, microRNAs, miRNA, biomarkers, liquid biopsy, therapeutics and therapy resistance. The search was limited to articles published from January 2000 to April 2024 and restricted to English-language studies. Original research articles, reviews and meta-analyses focused on the role of exosomes in lung cancer diagnosis and therapy were included, while conference abstracts, editorials, letters and unrelated studies were excluded.

Study selection was independently performed by two reviewers (J.R.S. and D.S.R.) based on titles and abstracts. Full texts were subsequently reviewed and any disagreements were resolved through discussion with senior reviewers (M.M.O., J.M.M.T. and J.A.D.M.). Any disagreements were resolved by consensus with senior reviewers ELI, DIN and M.D.V.A. Additional relevant articles were identified by screening the reference lists of selected studies. Only peer-reviewed and published articles were considered for inclusion. A structured summary of the search strategy is presented in Table 1.

Current challenges in lung cancer diagnosis and treatment

According to the latest global estimates from the World Health Organization, 2.5 million cases of lung cancer were diagnosed worldwide in 2022, making it the second most frequently diagnosed cancer (12% of all cases) and the leading cause of cancer-related mortality (18.7%, representing 1.8 million deaths) (15).

Globally, lung cancer remains the leading cause of cancer incidence and mortality among men. In women, it ranks third in incidence, following breast and colorectal cancer and second in cancer-related mortality, after breast cancer (16).

A downward trend in lung and bladder cancer incidence has been observed among men, likely reflecting the decline in tobacco use. In contrast, lung cancer incidence among women continues to rise, with the 2023 rate reported to be three times higher than in 2021. This divergence may reflect historical patterns in tobacco use: peak smoking prevalence in men occurred in those born between 1950 and 1959, while widespread smoking among women did not emerge until the 1960s (17,18).

Clinically, lung cancer often presents with nonspecific symptoms or minimal clinical expression, with severity typically increasing as the disease advances. Up to 25% of patients are asymptomatic at the time of diagnosis (4,19).

Because of its rapid progression and tendency for dissemination, lung cancer is rarely diagnosed at a resectable or limited stage occurring in fewer than 30% of cases (2,20).

Screening

Screening programs have been proposed to detect lung cancer at very early stages and thus increase survival rates (21,22). Although no organized national screening strategies exist across Europe, screening is recommended for very high-risk individuals (21,23). In the United States, low-dose computed tomography (LDCT) is performed in patients aged 55–80 years with a smoking history of more than 20 pack-years who are current smokers (21).

The NLST (National Lung Cancer Screening Trial) and NELSON (Dutch-Belgian Randomized Lung Cancer Screening Trial) studies provide the strongest evidence supporting LDCT screening (21,24,25). The NLST showed a 20% reduction in lung cancer-specific mortality after three annual rounds of LDCT screening compared to chest radiography, with a number needed to screen (NNS) of 320. The NELSON trial, with a different screening interval, reported a 25% reduction in lung cancer mortality after 10 years, with an NNS of 130 (21,24,26). Nevertheless, screening programs are associated with potential harms, including incidental findings, overdiagnosis, overtreatment, radiation exposure and increased patient anxiety; notably, the NELSON trial reported a 9% overdiagnosis rate after 11 years of follow-up (26).

Survival

In the United States, the 5-year survival rate for lung cancer is approximately 23% (27). In Spain, survival rates are 12.7% for men and 17.6% for women (18). Traditionally, 5-year survival has been used as a proxy for medium-term prognosis and, in some contexts, equated with cure. However, the biological behavior of lung cancer and clinical experience suggest that this metric is imprecise, as late recurrences are not uncommon. This underscores the need for prolonged and comprehensive follow-up (20,28,29).

It is also important to recognize that current therapies may induce periods disease chronicity. In a long-term follow-up study by Hubbard et al. involving a large cohort of lung cancer patients monitored for up to 18 years, disease-specific survival was found to decline progressively over time. Notably, among patients who remained disease-free for more than 10 years, 40.6% ultimately died from lung cancer-related causes. In terms of overall survival, only 24.3% of the cohort reached the end of the study period (29).

These findings, combined with the high disease burden and the significant loss of life years, highlight the urgent need for improved strategies enabling early detection, long-term monitoring and timely identification of recurrence.

EVs and their potential

EVs are a heterogeneous group of membrane-bound structures that play a critical role in cell-to-cell communication. They include exosomes, microvesicles and apoptotic bodies (30). EVs are present in most biological fluids, with the highest concentrations found in plasma and serum (31-33). They are released by nearly all mammalian cells, both under physiological and pathological conditions (34).

Exosomes, typically ranging from 40 to 150 nanometers in diameter, were first described by Johnstone et al. (35) in the 1980s. Figure 1 provides a schematic overview of their biogenesis and cargo. Exosome formation begins with the inward budding of the plasma membrane, followed by fusion with intracellular vesicles. The resulting compartments may either undergo degradation or contribute to the formation of a mature endosome. When these endosomes contain internal vesicles, they are referred to as multivesicular bodies (MVBs), which can subsequently fuse with the plasma membrane to release exosome into the extracellular space (11,13,36-44).

Figure 1 Exosome biogenesis and contents. Created using BioRender.com. MVB, multivesicular body.

Exosome formation and cargo

MVBs are formed through tightly regulated processes involving the endosomal sorting complex required for transport (ESCRT) and associated proteins. The ESCRT machinery comprises four sequentially acting protein complexes—ESCRT-0, ESCRT-I, ESCRT-II and ESCRT-III (34,45-47). ESCRT-0 recognizes and sequesters ubiquitinated cargo via interaction with phosphatidylinositol 3-phosphate in the endosomal membrane and recruits ESCRT-I through its TSG101 subunit (34,47). ESCRT-I and ESCRT-II initiate membrane deformation and budding, while ESCRT-III mediates the final scission of intraluminal vesicles (48-50). Accessory proteins such as Alix, Bro1 and VPS4 further support this process, with VPS4 playing a crucial role in ESCRT recycling and membrane fission process (34,46,48,51,52).

Beyond the canonical ESCRT-dependent pathway, ESCRT-independent mechanisms of exosome biogenesis include tetraspanin-enriched microdomains (TEMs)—notably CD9, CD63 and CD81—as well as ceramide-dependent pathways mediated by neutral sphingomyelinases (34,53). Additional molecules such as flotillin, phospholipase D2 (PLD2), ARF6 and lipid raft components contribute to this alternative trafficking. These redundant and adaptable pathways suggests that exosome formation can be modulated by cell type, physiological state and external stimuli (34,36,54).

The exosomal cargo is highly diverse and selectively packaged. It includes nucleic acids, lipids, proteins or amino acids and metabolites (32). In cancer, the sorting of this cargo is often altered due to modifications in ESCRT function, resulting in vesicles with distinct contents and biological effects on recipient cells (36). Common protein constituents of exosomes include molecules involved in MVB formation (e.g., Alix, TSG101, clathrin), membrane trafficking (e.g., Rab GTPases, flotillins, annexins, ARF6) and membrane organization (e.g., tetraspanins CD9, CD63, CD81) (10,55). In certain immune cell-derived exosomes, major histocompatibility complex (MHC) class II molecules are also present, indicating a potential role in antigen presentation (34,38).

In terms of nucleic acids, exosomes carry a variety of RNA species, among which messenger RNA (mRNA) and microRNA (miRNA) are the most extensively characterized. MiRNAs are small non-coding RNAs (18 to 24 nucleotides) that regulate gene expression and influence critical processes, including proliferation, apoptosis, cell differentiation and metabolism. Their stability in circulation, resistance to enzymatic degradation and temperature and distinct expression profile compared to donor cells make them ideal candidates for biomarker development (34,55). Table 2 presents all miRNAs included in this review along with their pathophysiological functions.

MiRNA loading into exosomes is a tightly regulated and selective process involving several mechanisms, including ceramide-dependent sorting via nSMase2, 3’ miRNA sequence motifs, RNA-binding proteins (e.g., hnRNPA2B1) and components of the RISC-loading complex (34,84). Tumor-derived exosomes often show a distinct RNA profile influenced by environmental stressors such as hypoxia and radiation (84).

Importantly, exosomal RNA (esRNA) is not a random subset of cytoplasmic RNA. Instead, it is actively sorted through interactions with RNA binding proteins (RBPs). Up to 30 RBPs have been identified in exosomes, with 20 forming stable complexes with esRNAs. For instance, hnRNPA2B1 binds to GGAG-rich motifs in specific miRNAs, thereby promoting their incorporation into exosomes, while YBX1 has been shown to facilitate the loading of miR-223 through direct recognition of sequence elements. Other RBPs, such as Ago2, also participate in the selective inclusion of particular miRNAs (85,86).

Major Vault Protein (MVP), in particular, plays a key role in RNA loading, as its silencing significantly reduces esRNA content. These findings support the concept that exosomes carry functional ribonucleoprotein complexes, essential for RNA stability and intercellular communication. Current evidence indicates that it contributes to the enrichment of oncogenic RNAs within exosomes, highlighting its importance in tumor progression (85,86).

In addition to RNA, exosomal DNA (exoDNA) has also been detected. Unlike RNA, exoDNA appears to be incorporated in a less selective manner and may reflect the entire genome of the cell of origin (34,87). exoDNA carries clinically relevant genetic alterations, including mutations in EGFR, KRAS, and TP53, thereby reflecting the mutational landscape of tumors such as NSCLC (88). In a recent study, therapeutically actionable EGFR mutations were detected in plasma-derived exoDNA with a sensitivity of 76.6% compared to tissue biopsy results, highlighting its reliability as a minimally invasive diagnostic tool. Importantly, detection rates were not significantly influenced by tumor stage, histological subtype, smoking status, age, or sex, underscoring the robustness of exoDNA analysis. These findings support the potential of exoDNA to complement or, in some contexts, substitute tissue biopsies for the early identification of clinically relevant mutations in NSCLC, thereby facilitating timely access to targeted therapies (89).

Exosome isolation

A wide range of methods has been developed for exosome isolation, each with distinct advantages and limitations (Table 3). Ultracentrifugation remains the most established technique due to its accessibility and ability to process large sample volumes. However, it is associated with low yield, potential exosome damage due to high g-forces and poor purity owing to the co-isolation of contaminants. Density gradient centrifugation improves purity but is time-consuming and impractical for clinical use. Ultrafiltration offers a faster, size-based separation although membrane clogging and loss of smaller vesicles limit its effectiveness. Polymer-based precipitation is widely used for its operational simplicity, yet it often results in co-precipitation of non-exosomal components, compromising purity. In contrast, size-exclusion chromatography (SEC) stands out for preserving exosome structure and enabling high purity, especially when combined with pre-filtration steps (90,91). Iodixanol density gradient centrifugation provides high-resolution separation based on buoyant density and is used when sample precision is essential (90,91).

Immunoaffinity-based isolation enables highly specific exosome capture via recognition of surface markers, allowing selective enrichment of disease-specific vesicles. However, its application is typically limited to small-scale analysis due to high costs, complexity and low throughput (90,91). No single isolation method is universally optimal. Instead, the choice of technique should be guided by the specific downstream application, balancing purity, yield, scalability and sample volume constraints (90).

Emerging microfluidic technologies offer integrated platforms capable of isolating, detecting and analyzing within a single device. These systems exploit a range of mechanisms—including physical properties (e.g., size and charge), biochemical interactions (e.g., immunoaffinity) and external forces (e.g., acoustic, electric, or magnetic)—to achieve label-free, high-throughput and often real-time exosome isolation. Their rapid processing, minimal reagent consumption and high-purity outputs make them particularly attractive for diagnostic applications (34,91,92).

Despite these advantages, current microfluidic approaches face several limitations. No existing platform simultaneously achieves high purity and high yield without requiring extensive off-chip sample preprocessing. Integration of exosome isolation with downstream molecular analysis remains underdeveloped, limiting true point-of-care potential. Technical barriers, including high fabrication costs, especially for sub-80 µm features requiring photolithography, hinder mass production. Moreover, many systems lack specificity for organ- or tissue-derived exosomes, which is essential for clinical relevance. Finally, the absence of standardized metrics such as recovery rate, purity and biological activity, impedes cross-platform comparison and broader adoption (93). Nonetheless, microfluidics holds great promise to streamline exosome workflows, reduce dependence on ultracentrifugation and enhance reproducibility in both research and clinical context (34,91,92).

A high level of exosome purity is necessary to ensure reproducibility and reliability of biomarker detection, although no universally accepted threshold has yet been established. In practice, a balance between purity and yield is often required, since techniques that provide very high purity are time-consuming and impractical for routine use, whereas faster approaches may compromise purity. In parallel, emerging microfluidic and biosensor-based platforms enable rapid or near “real-time” exosome isolation and analysis. While these technologies hold great promise for clinical application and point-of-care diagnostics, they are still under development and are not yet integrated into standard diagnostic workflows (91).

Exosomes and lung cancer

Several studies have demonstrated elevated exosome levels in patients with lung cancer. For instance, Rabinowits et al. reported a significant increase in plasma-derived exosomes in patients with lung adenocarcinoma compared to healthy controls (94). Similarly, Rodríguez et al. found higher concentrations of exosomes in bronchoalveolar lavage fluid from lung cancer patients relative to healthy individuals (95). Interestingly, Zhong et al. showed that smoking promotes exosome release both locally and systematically. These exosomes were implicated in processes such as angiogenesis, endothelial dysfunction, tissue remodeling, inflammation, oxidative stress, fibrosis and thrombosis (8,96).

Exosomes are now recognized as central players in tumor pathophysiology, being actively secreted by malignant cells and contributing to various oncogenic processes. In lung cancer specifically, exosomes are involved in tumor initiation, progression and angiogenesis through endothelial cell stimulation as illustrated in Figure 2. Moreover, they play a pivotal role in metastatic dissemination by modifying the tumor microenvironment and preparing pre-metastatic niches (8,9,32,97,98).

Figure 2 Processes involving exosomal miRNAs in the pathogenesis and progression of lung cancer. Created using BioRender.com. EMT, epithelial-mesenchymal transition; miRNA, microRNA; NK, natural killer; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor.

Exosomes in the early detection of lung cancer

Among the various exosomal components, miRNAs have garnered particular attention due to their dysregulated expression profiles in several tumors, including breast, prostate and ovarian (8).

In lung cancer, numerous exosomal miRNAs have been reported to be significantly elevated in patients compared to healthy control. These include miR-17-3p, miR-21, miR-30b, miR-30c, miR-103, miR-106a, miR-122 miR-146, miR-155, miR-199, miR-192, miR-195, miR-203, miR-205, miR-210, miR-212, miR-214, miR-221, miR-222, miR-500a-3p, miR-501-3p and miR-502-3p (8,56-58,64,94).

Several of these miRNAs have shown potential as biomarkers for the early diagnosis of NSCLC, including miR-10b-5b, miR-15, miR-30a-3p, miR-30e-3p, miR-126, miR-320b and miR-361 (65,67). MiR-1290 and miR-29c-3p have also emerged as promising candidates, not only for early detection but also for distinguishing between NSCLC and SCLC (69). Tian et al. further reported the overexpression of miR-21b and miR-21 in NSCLC patients (59).

However, despite the growing number of studies, significant heterogeneity exists regarding the specific miRNAs identified as diagnostic markers. Notably, the specific miRNAs reported as disease-associated often vary considerably across studies, with certain signatures being highlighted in one investigation but not replicated in others. This inconsistency likely reflects differences in patient cohorts, methodologies, and analytical platforms, but it also underscores the lack of consensus in the field. Moreover, most reported miRNA biomarkers remain at the stage of initial discovery and await rigorous validation in large, independent cohorts. As a result, it remains uncertain whether these candidate miRNAs will ultimately prove to be reliable or clinically useful biomarkers.

Some miRNAs appear to be subtype specific. For instance, miR-30a-3p, miR-100, miR-139, miR-151a, miR-154-3p, miR-200b, miR-378a, miR-379 and miR-629 have been identified as potential biomarkers for lung adenocarcinoma (66). Moreover, early detection markers include miR-181, miR-30a-3p, miR-30e-3p, miR-361, miR-342, miR-486 and miR-574 for adenocarcinoma and miR-10b, miR-15b and miR-320b, for squamous cell carcinoma (59,65,70). Additionally, miR-151a-3p and miR-877 have been associated with a higher risk of bone metastases in lung cancer patients (74).

Multi-miRNA signatures have demonstrated superior diagnostic performance compared to individual miRNA markers, suggesting that combinatorial profiling enhances specificity and sensitivity. For instance, panels including miR-126-3p, miR-221-3p, let-7b and miR-222-3p for adenocarcinoma and miR-21, miR-221-3p, let-7b and miR-9 for squamous cell carcinoma, achieved area under the curve (AUC) values of 0.764 and 0.842, respectively. Similarly, miR-1290 and miR-29c-3p displayed excellent discriminatory capacity (AUCs >0.9) between lung cancer and benign pulmonary disease (6,60).

These findings are especially compelling as they offer not only sensitivity and specificity but also translational value. For example, miR-4497 have also been associated with disease stage and response to surgery, adding prognostic utility to their diagnostic function (79). The consistency of results across cancer subtypes and cohorts highlights the promise of suggests the potential for clinical implementation of miRNA-based assays, pending further validation in larger populations and diverse clinical settings (6).

Malignant pleural effusion is a common complication in lung cancer patients. While traditionally used for cytological assessment it contains exosomes that offer molecular insights. Distinct exosomal miRNA profiles have been shown to distinguish malignant effusions from those of infectious origin. Notably, miR-21 and miR-30a have been identified as candidate markers for malignancy (8,99) and miR-12 has been associated with disease recurrence (58).

Beyond miRNAs, exosomal membrane proteins are emerging as relevant biomarker with prognostic implications. Noteworthy examples include NY-ESO, PLAP, EGFR, Alix and EpCAM (8,100,101). NY-ESO (New York Esophageal Squamous Cell Carcinoma) is expressed in a wide range of tumors but not in normal tissues, making it a highly specific prognostic indicator of NSCLC. Placental alkaline phosphatase (PLAP) is elevated in advanced stages of disease and correlated with poor prognosis in NSCLC. Exosomal EGFR levels may inform treatment decisions by identifying candidates for targeted therapies (8,101). Alix, a key regulator of exosome biogenesis, has been linked to increase tumor aggressiveness and worse clinical outcomes. Epithelial cell adhesion molecule (EpCAM) is associated with metastatic disease and reduced survival in NSCLC patients (8,100).

Exosomes and tumor angiogenesis

Angiogenesis is a critical driver of tumor growth and metastasis. As tumors expand, their demand for oxygen surpasses the capacity of the exiting vasculature, leading to hypoxia. This hypoxic environment induces the expression of pro-angiogenic factors and triggers the formation of the disorganized vasculature characteristic of malignant tissues. Exosomes have been implicated in this process, particularly through the induction of hypoxia-inducible factors (HIFs), specifically the activation of HIF-1α and HIF-2α (8,102).

Under hypoxic conditions, tumor cells release exosomes enriched in specific miRNAs that modulate angiogenesis. For example, hypoxia-induced exosomal miR-23 targets ZO-1 and prolyl hydroxylase, promoting both angiogenesis and vascular permeability (9,61). Similarly, miR-619, upregulated in hypoxic lung cancer cells, facilitates angiogenesis by inhibiting calcineurin regulatory factors 1 and 4 (55,71).

Other exosomal miRNAs also contribute to neovascularization. For instance, miR-142-3p, derived from lung adenocarcinoma cells, promotes metastasis by transferring through exosomes to endothelial cells and inhibiting transforming growth factor-β receptor I (TGF-βR I) (55,103). Additionally, miR-21, whose expression is elevated in smokers, is transferred via exosomes between epithelial cells. This promotes STAT3 activation, leading to increased vascular endothelial growth factor (VEGF) production, this enhancing angiogenesis and malignant transformation (61).

Several additional exosomal miRNAs are involved in angiogenic regulation, including miR-296, miR-132, miR-126 and miR-210, many of which are downstream targets of VEGF (8,55,75). Exosome-mediated delivery of miR-9 also enhances endothelial cell migration downregulating SOCS5 and activating JAK-STAT pathway, further supporting neovascularization (8,55,75,104). Additionally, tumor-associated macrophage-derived exosomes enriched in miR-942 promote metastasis and angiogenesis in lung adenocarcinoma by downregulating FOXO1 and activating β-catenin signaling, highlighting their therapeutic potential (72).

An emerging body of evidence underscores the role of EVs, particularly tumor derived EVs (T-EVs), in mediating resistance to anti-angiogenic therapies (AAT) (105). Despite the clinical use of VEGF/VEGFR inhibitors such as bevacizumab, resistance frequently develops (105-107). EVs contribute to AAT resistance by presenting VEGF in membrane-associated forms, such as VEGF90k and VEGF189, which evade neutralization by anti-VEGF antibodies. Moreover, chaperone proteins like Hsp90 and surface heparan sulfate proteoglycans on EVs stabilize of vesicle-associated VEGF, maintaining angiogenic signaling despite therapeutic inhibition. The secretion of pro-angiogenic EVs is further upregulated under therapeutic pressure, allowing tumor cells to bypass VEGF blockade. Notably, EVs derived from non-tumor cells in the tumor microenvironment, including cancer-associated fibroblasts (CAFs) and tumor-associated macrophages, also contribute to resistance mechanisms (105).

Exosomes and the origin of metastases

Metastasis remains a major cause of poor prognosis and mortality in lung cancer patients and exosomes play a critical role in several mechanisms underlying this process. A well-characterized pathway facilitating metastasis is the epithelial-mesenchymal transition (EMT), a morphogenetic process in which epithelial cells lose intercellular adhesion, reduce cytoskeleton keratin levels and increase mesenchymal markers such as vimentin. This transition imparts migratory and invasive capabilities to tumor cells, enabling dissemination to distant organs (9,97). In lung cancer, hypoxic conditions have been shown to active the STAT3 signaling pathway, leading to the upregulation of EMT markers (9,108).

Exosomal cargo actively contributes to these phenotypic changes. For instance, exosomes derived from NSCLC contain miR-3157-3p, which downregulates the expression of TIMP2, KLF2, ZO-1 and occludin while upregulating VEGF, matrix metalloproteinase (MMP)2 and MMP9, thereby promoting both metastasis and angiogenesis (9,73).

CAFs, key components of the tumor stroma, modulate the tumor microenvironment through the secretion of cytokines and exosomes. CAF-derived miR-210 has been linked to the activation of the PTEN/PI3K/Akt pathway, promoting invasion and metastasis in NSCLC (55,76). Similarly, miR-210-3p, secreted by lung cancer stem cells, can inhibit the function of the CAF growth factor receptor, thereby suppressing its activity. This leads to upregulation of mesenchymal markers (N-cadherin, vimentin and MMP1 and MMP9) and downregulation of epithelial cadherin (E-cadherin), further facilitating EMT and metastasic dissemination (109).

In addition, other exosomal miRNAs, including miR-122, miR-494, miR-542-3p, miR-193-3p, miR-5100, miR-96, miR-660, miR-499a, miR-208a, miR-222-3p, miR-103a and miR-192, have also been associated with tumor proliferation and distant metastasis (8,55,77,78).

Exosomes and immune regulation

The ability of tumor cells to evade immune surveillance is a major obstacle to the success of immune therapy. Exosome-mediated signaling plays a critical role in molecular recognition and the activation of downstream immune pathways (55,110,111).

Tumor-derived exosomes exert predominantly immunosuppressive effects by inhibiting the proliferation and function of immune effector cells (55). In contrast, exosomes originating from immune cells can inhibit tumor progression by promoting inflammation and immune activation (110,111).

These vesicles can carry immunosuppressive molecules such as checkpoint receptor ligands (e.g., PD-L1), cell death receptor ligands, inhibitory cytokines and ectoenzymes. Conversely, they may also transport immunostimulatory signals, including tumor antigens and molecules like Hsp70 and BAT3, which promote the secretion of IFN-γ and TNF-α in natural killer (NK) cells (110,111). In the lung, which is highly exposed to environmental antigens, smoke and pathogens, exosomes are implicated in inflammatory processes that may ultimately lead to oncogenic transformation (111). They induce apoptosis of activated CD8⁺ T lymphocytes via FasL, TRAIL and PD-L1 expression (112). They also impair NK cell cytotoxicity by downregulating the activating receptor NKG2D and by inducing the expression of TIM-3, a marker of NK cell exhaustion. Moreover, exosomes inhibit dendritic cell maturation and activation, thereby impairing antigen presentation and subsequent T-cell priming (12,112).

In addition to direct immune suppression, exosomes contribute to the establishment of an immunosuppressive tumor microenvironment. They promote the expansion of regulatory B and T lymphocytes and drive the polarization of macrophages toward a tumorigenic M2 phenotype through the transfer of miRNAs and proteins such as IL-6, STAT3 and TGF-β1 (8,12,112).

Furthermore, exosomes are implicated in the development of paraneoplastic syndromes and therapy resistance (8,32,54). Key exosomal miRNAs involved in these processes include miR-21, miR-29, miR-23a and miR-210 (55,76).

Exosomes and therapy resistance

Therapeutic resistance is one of the principal causes of cancer recurrence and disease progression. Increasing evidence suggests that exosomes and their cargo play a critical role in mediating resistance to antitumor therapies (11,13,39-44,105).

Cisplatin is widely used in lung cancer therapy; however, resistance frequently develops. Exosomal transfer of miR-21 has been shown to induce cisplatin resistance in A549 cells and can confer resistance to previously naïve cells through vesicle-mediated transmission (62). Significant differences in the levels of several exosomal miRNAs, including miR-425-3p, miR-1273h, miR-4755, miR-9, miR-146a and miR-215 have been observed between cisplatin-sensitive and cisplatin-resistant patients. Notably, low miR-146 levels in advanced NSCLC are associated with higher recurrence rates (55,83). Further studies have linked exosomal miR-425-3p to cisplatin resistance via the promotion of tumor cell autophagy through Akt pathway activation (43,55). Similarly, increased miR-96 expression has been associated with elevated cisplatin resistance and poor prognosis in invasive lung cancer, mediated through the targeting of LMO7 (41,55). Additionally, cisplatin-resistant NSCLC cells have been shown to secrete PKM2-enriched exosomes that can transfer resistance traits to sensitive cells (39).

Exosome-mediated signaling also contributes to resistance against epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Exosomal transfer of miR-21 reduces sensitivity to gefitinib (8), while miRNA-522-3p, secreted by lung cancer cells expressing the EGFR T790M mutation, promotes gefitinib resistance through activation of the PI3K-Akt pathway (44). Furthermore, miR-99a has been implicated in resistance to both cisplatin and gefitinib via mTOR pathway, enhancing cell survival and inhibiting apoptosis (82). Additional exosomal miRNAs, such as miR-184, miR-3913, miR-323-3p, miR-1468-3p, miR-5189 and miR-6513, have been associated with resistance to osimertinib in NSCLC patients (11,42).

Recent evidence also highlights the predictive value of exosomal miRNAs in immunotherapy response. Specific circulating and EVs miRNAs, such as miR-199a-3p, miR-21 and miR-28, have shown superior predictive performance (AUC up to 0.925) compared to PD-L1 immunohistochemistry in identifying responders to anti-PD-1/PD-L1 immunotherapy in NSCLC (63).

Beyond these examples, a broader set of miRNAs, including miR-10b, miR-17-92, miR-34a, miR-100, miR-125b, miR-126, miR-133b, miR-146a, miR-221, miR-222-3p and miR-1246, have also implicated in promoting drug resistance (8,13,55,68,80,81).

The therapeutic potential of exosomes as a delivery agent

In addition to their roles in tumor progression and immune modulation, exosomes have emerged as highly promising therapeutic delivery vehicles, owing to their capacity for targeted interaction with specific cells (Figure 3). They exhibit high biocompatibility, achieving up to 30-fold greater cellular uptake compared to liposomes or nanoparticles. Moreover, exosomes are stable in systemic circulation and can endure extreme physiological conditions, such as acidic blood pH. Their application may also reduce treatment-associated toxicity, particularly for agents with low solubility (8,113).

Figure 3 Exosome-based therapeutic approaches in cancer: delivery systems and therapeutic targets. Created using BioRender.com. ADAPT, Adaptive Dialysis-like Affinity Platform Technology; miRNA, microRNA; siRNA, small interfering RNA.

Exosomes can transport a wide range of therapeutic cargos, including small RNAs, oligonucleotides, chemotherapeutic agents and immune modulators (32,36,54). Preclinical studies using exosome-encapsulated paclitaxel and docetaxel have already demonstrated improved therapeutic efficacy compared to previous therapies (8,114).

Therapeutic loading into exosomes can be achieved through direct methods, such as electroporation, extrusion and sonication, or indirectly by genetically or pharmacologically engineering donor cells. To optimize therapeutic efficacy, exosomes often require further modification to enhance targeting specificity and biodistribution. This can be accomplished by incorporating ligands, antibodies, or other targeting molecules onto their surface, enabling selective binding to specific cellular receptors (8,14).

The therapeutic potential of exosomes as a target for treatment

Given their well-established role as facilitators of tumor progression and mediators of intercellular communication in various pathological processes, several experimental strategies have been proposed to therapeutically target exosomes (Figure 3). One such approach involves the removal of circulating exosomes through a dialysis-like procedure using a device called Aethlon ADAPT (Adaptive Dialysis-like Affinity Platform Technology). This technique involves passing blood through a specialized matrix tailored with specific aptamers, monoclonal antibodies, or other ligands designed to capture targeted exosomes. However, the potential adverse effects—particularly those related to the physiological roles of exosomes in immune regulation—remain unclear and the overall safety of this method has yet to be firmly established (8).

Another promising strategy focuses on inhibiting exosome production or secretion of exosomes by tumor cells using genetic approaches. For instance, the use of short interfering RNA (siRNA) has been explored to selectively target tumor cells expressing PD-L1, resulting in the inhibition of PD-L1 expression and the induction of apoptosis (8,115).

Targeting specific exosomal miRNAs also represents a viable therapeutic avenue. For example, miR-21 has been implicated in osteoclastogenesis and the facilitation of lung cancer metastasis, suggesting its inhibition could effectively suppress disease progression (116). Similarly, miR-96, which has been associated with tumor proliferation, migration and therapy resistance, has emerged as another therapeutic target (41,55).

Conclusions

Exosomes have emerged as highly dynamic and functionally versatile mediators in lung cancer biology, offering novel opportunities for diagnosis, prognosis and therapeutic intervention. Their cargo, particularly exosome-derived miRNAs, reflects the molecular landscape of the tumor and shows strong potential as a minimally invasive biomarker for early detection, disease stratification and treatment monitoring. Beyond their role as biomarkers, exosomes actively contribute to key oncogenic processes, including angiogenesis, immune modulation, metastasis and the development of resistance to chemotherapeutic agents and targeted therapies.

As research advances, the therapeutic potential of exosomes continues to expand, encompassing applications as delivery vectors and direct therapeutic targets. However, the clinical translation of exosome-based technologies faces several critical challenges, including the need for standardized isolation and characterized methods, large-scale validation of biomarker panels and thorough evaluation of the safety implications associated with exosome manipulation or depletion. With continued progress in microfluidics, bioengineering and molecular profiling, exosomes are poised to transform the clinical management of lung cancer, bringing the vision of personalized, precision medicine closer to reality.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-557/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-557/prf

Funding: This work was supported by Instituto de Salud Carlos III, Ministry of Health, Spain and the European Regional Development Fund (FEDER) (No. CD22/00033), Department of Science and Universities, Government of Aragon, Spain (No. CUS/1638/2022; B22_23R) and IIS Aragón, Spain (No. INTRAMURAL23/FSE-I/01).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-557/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Howlader N, Forjaz G, Mooradian MJ, et al. The Effect of Advances in Lung-Cancer Treatment on Population Mortality. N Engl J Med 2020;383:640-9. [Crossref] [PubMed]
2. Kratzer TB, Bandi P, Freedman ND, et al. Lung cancer statistics, 2023. Cancer 2024;130:1330-48. [Crossref] [PubMed]
3. Tan DS, Camilleri-Broët S, Tan EH, et al. Intertumor heterogeneity of non-small-cell lung carcinomas revealed by multiplexed mutation profiling and integrative genomics. Int J Cancer 2014;135:1092-100. [Crossref] [PubMed]
4. Jiang D, Wang Z, Li H, et al. Experiences of patient delay among lung cancer patients in South China. BMC Cancer 2024;24:1527. [Crossref] [PubMed]
5. Detterbeck FC, Mazzone PJ, Naidich DP, et al. Screening for lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013;143:e78S-e92S.
6. Martínez-Espinosa I, Serrato JA, Cabello-Gutiérrez C, et al. Exosome-Derived miRNAs in Liquid Biopsy for Lung Cancer. Life (Basel) 2024;14:1608. [Crossref] [PubMed]
7. Gupta R, Radicioni G, Abdelwahab S, et al. Intercellular Communication between Airway Epithelial Cells Is Mediated by Exosome-Like Vesicles. Am J Respir Cell Mol Biol 2019;60:209-20. [Crossref] [PubMed]
8. Abdul Manap AS, Ngwenya FM, Kalai Selvan M, et al. Lung cancer cell-derived exosomes: progress on pivotal role and its application in diagnostic and therapeutic potential. Front Oncol 2024;14:1459178. [Crossref] [PubMed]
9. Zhao J, Li X, Liu L, et al. Exosomes in lung cancer metastasis, diagnosis, and immunologically relevant advances. Front Immunol 2023;14:1326667. [Crossref] [PubMed]
10. Cunha E, Rocha K, Ying W, Olefsky JM. Exosome-Mediated Impact on Systemic Metabolism. Annu Rev Physiol 2024;86:225-53. [Crossref] [PubMed]
11. Li X, Chen C, Wang Z, et al. Elevated exosome-derived miRNAs predict osimertinib resistance in non-small cell lung cancer. Cancer Cell Int 2021;21:428. [Crossref] [PubMed]
12. Luo C, Xin H, Zhou Z, et al. Tumor-derived exosomes induce immunosuppressive macrophages to foster intrahepatic cholangiocarcinoma progression. Hepatology 2022;76:982-99. [Crossref] [PubMed]
13. Patra SK, Sahoo RK, Biswal S, et al. Enigmatic exosomal connection in lung cancer drug resistance. Mol Ther Nucleic Acids 2024;35:102177. [Crossref] [PubMed]
14. Iqbal Z, Rehman K, Mahmood A, et al. Exosome for mRNA delivery: strategies and therapeutic applications. J Nanobiotechnology 2024;22:395. [Crossref] [PubMed]
15. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2024;74:229-63. [Crossref] [PubMed]
16. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021;71:209-49. [Crossref] [PubMed]
17. Remon J, Reguart N, García-Campelo R, et al. Lung Cancer in Spain. J Thorac Oncol 2021;16:197-204. [Crossref] [PubMed]
18. Sociedad Española de Oncología Médica (SEOM). Las cifras del cáncer en España 2023 [Internet]. 2023 [cited 2024 Jan 20]. Available online: https://seom.org/images/Las_cifras_del_Cancer_en_Espana_2023.pdf
19. Ost DE, Jim Yeung SC, Tanoue LT, et al. Clinical and organizational factors in the initial evaluation of patients with lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013;143:e121S-e141S.
20. Dómine M, Moran T, Isla D, et al. SEOM clinical guidelines for the treatment of small-cell lung cancer (SCLC) (2019). Clin Transl Oncol 2020;22:245-55. [Crossref] [PubMed]
21. Wolf AMD, Oeffinger KC, Shih TY, et al. Screening for lung cancer: 2023 guideline update from the American Cancer Society. CA Cancer J Clin 2024;74:50-81. [Crossref] [PubMed]
22. Mazzone PJ, Silvestri GA, Souter LH, et al. Screening for Lung Cancer: CHEST Guideline and Expert Panel Report. Chest 2021;160:e427-94. [Crossref] [PubMed]
23. de Koning HJ, van der Aalst CM, de Jong PA, et al. Reduced Lung-Cancer Mortality with Volume CT Screening in a Randomized Trial. N Engl J Med 2020;382:503-13. [Crossref] [PubMed]
24. Pinsky PF, Church TR, Izmirlian G, et al. The National Lung Screening Trial: results stratified by demographics, smoking history, and lung cancer histology. Cancer 2013;119:3976-83. [Crossref] [PubMed]
25. Lung Cancer Incidence and Mortality with Extended Follow-up in the National Lung Screening Trial. J Thorac Oncol 2019;14:1732-42. [Crossref] [PubMed]
26. Yousaf-Khan U, van der Aalst C, de Jong PA, et al. Final screening round of the NELSON lung cancer screening trial: the effect of a 2.5-year screening interval. Thorax 2017;72:48-56. [Crossref] [PubMed]
27. Siegel RL, Miller KD, Wagle NS, et al. Cancer statistics, 2023. CA Cancer J Clin 2023;73:17-48. [Crossref] [PubMed]
28. Majem M, Juan O, Insa A, et al. SEOM clinical guidelines for the treatment of non-small cell lung cancer (2018). Clin Transl Oncol 2019;21:3-17. [Crossref] [PubMed]
29. Hubbard MO, Fu P, Margevicius S, et al. Five-year survival does not equal cure in non-small cell lung cancer: a Surveillance, Epidemiology, and End Results-based analysis of variables affecting 10- to 18-year survival. J Thorac Cardiovasc Surg 2012;143:1307-13. [Crossref] [PubMed]
30. Pastor L, Vera E, Marin JM, et al. Extracellular Vesicles from Airway Secretions: New Insights in Lung Diseases. Int J Mol Sci 2021;22:583. [Crossref] [PubMed]
31. Crossland RE, Norden J, Bibby LA, et al. Evaluation of optimal extracellular vesicle small RNA isolation and qRT-PCR normalisation for serum and urine. J Immunol Methods 2016;429:39-49. [Crossref] [PubMed]
32. Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science 2020;367:eaau6977. [Crossref] [PubMed]
33. Muller L, Hong CS, Stolz DB, et al. Isolation of biologically-active exosomes from human plasma. J Immunol Methods 2014;411:55-65. [Crossref] [PubMed]
34. Tschuschke M, Kocherova I, Bryja A, et al. Inclusion Biogenesis, Methods of Isolation and Clinical Application of Human Cellular Exosomes. J Clin Med 2020;9:436. [Crossref] [PubMed]
35. Johnstone RM, Adam M, Hammond JR, et al. Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). J Biol Chem 1987;262:9412-20.
36. Cui S, Cheng Z, Qin W, et al. Exosomes as a liquid biopsy for lung cancer. Lung Cancer 2018;116:46-54. [Crossref] [PubMed]
37. Krylova SV, Feng D. The Machinery of Exosomes: Biogenesis, Release, and Uptake. Int J Mol Sci 2023;24:1337. [Crossref] [PubMed]
38. Doyle LM, Wang MZ. Overview of Extracellular Vesicles, Their Origin, Composition, Purpose, and Methods for Exosome Isolation and Analysis. Cells 2019;8:727. [Crossref] [PubMed]
39. Wang D, Zhao C, Xu F, et al. Cisplatin-resistant NSCLC cells induced by hypoxia transmit resistance to sensitive cells through exosomal PKM2. Theranostics 2021;11:2860-75. [Crossref] [PubMed]
40. Cheng HY, Su GL, Wu YX, et al. Extracellular vesicles in anti-tumor drug resistance: Mechanisms and therapeutic prospects. J Pharm Anal 2024;14:100920. [Crossref] [PubMed]
41. Wu H, Zhou J, Mei S, et al. Circulating exosomal microRNA-96 promotes cell proliferation, migration and drug resistance by targeting LMO7. J Cell Mol Med 2017;21:1228-36. [Crossref] [PubMed]
42. Janpipatkul K, Trachu N, Watcharenwong P, et al. Exosomal microRNAs as potential biomarkers for osimertinib resistance of non-small cell lung cancer patients. Cancer Biomark 2021;31:281-94. [Crossref] [PubMed]
43. Ma Y, Yuwen D, Chen J, et al. Exosomal Transfer Of Cisplatin-Induced miR-425-3p Confers Cisplatin Resistance In NSCLC Through Activating Autophagy. Int J Nanomedicine 2019;14:8121-32. [Crossref] [PubMed]
44. Liu X, Jiang T, Li X, et al. Exosomes transmit T790M mutation-induced resistance in EGFR-mutant NSCLC by activating PI3K/AKT signalling pathway. J Cell Mol Med 2020;24:1529-40. [Crossref] [PubMed]
45. Hanson PI, Cashikar A. Multivesicular body morphogenesis. Annu Rev Cell Dev Biol 2012;28:337-62. [Crossref] [PubMed]
46. Winter V, Hauser MT. Exploring the ESCRTing machinery in eukaryotes. Trends Plant Sci 2006;11:115-23. [Crossref] [PubMed]
47. Morvan J, Rinaldi B, Friant S. Pkh1/2-dependent phosphorylation of Vps27 regulates ESCRT-I recruitment to endosomes. Mol Biol Cell 2012;23:4054-64. [Crossref] [PubMed]
48. Juan T, Fürthauer M. Biogenesis and function of ESCRT-dependent extracellular vesicles. Semin Cell Dev Biol 2018;74:66-77. [Crossref] [PubMed]
49. Tang S, Buchkovich NJ, Henne WM, et al. ESCRT-III activation by parallel action of ESCRT-I/II and ESCRT-0/Bro1 during MVB biogenesis. Elife 2016;5:e15507. [Crossref] [PubMed]
50. Larios J, Mercier V, Roux A, et al. ALIX- and ESCRT-III-dependent sorting of tetraspanins to exosomes. J Cell Biol 2020;219:e201904113. [Crossref] [PubMed]
51. Mathieu M, Martin-Jaular L, Lavieu G, et al. Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication. Nat Cell Biol 2019;21:9-17. [Crossref] [PubMed]
52. Hurley JH, Emr SD. The ESCRT complexes: structure and mechanism of a membrane-trafficking network. Annu Rev Biophys Biomol Struct 2006;35:277-98. [Crossref] [PubMed]
53. Schulze U, Brast S, Grabner A, et al. Tetraspanin CD63 controls basolateral sorting of organic cation transporter 2 in renal proximal tubules. FASEB J 2017;31:1421-33. [Crossref] [PubMed]
54. Xu K, Zhang C, Du T, et al. Progress of exosomes in the diagnosis and treatment of lung cancer. Biomed Pharmacother 2021;134:111111. [Crossref] [PubMed]
55. Zhang Z, Lin F, Wu W, et al. Exosomal microRNAs in lung cancer: a narrative review. Transl Cancer Res 2024;13:3090-105. [Crossref] [PubMed]
56. Yanaihara N, Caplen N, Bowman E, et al. Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell 2006;9:189-98. [Crossref] [PubMed]
57. Giallombardo M, Chacártegui Borrás J, Castiglia M, et al. Exosomal miRNA Analysis in Non-small Cell Lung Cancer (NSCLC) Patients’ Plasma Through qPCR: A Feasible Liquid Biopsy Tool. J Vis Exp 2016;111:53900. [Crossref] [PubMed]
58. Munagala R, Aqil F, Gupta RC. Exosomal miRNAs as biomarkers of recurrent lung cancer. Tumour Biol 2016;37:10703-14. [Crossref] [PubMed]
59. Tian F, Shen Y, Chen Z, et al. Aberrant miR-181b-5p and miR-486-5p expression in serum and tissue of non-small cell lung cancer. Gene 2016;591:338-43. [Crossref] [PubMed]
60. Hassanin AAI, Ramos KS. Circulating Exosomal miRNA Profiles in Non-Small Cell Lung Cancers. Cells 2024;13:1562. [Crossref] [PubMed]
61. Hsu YL, Hung JY, Chang WA, et al. Hypoxic lung cancer-secreted exosomal miR-23a increased angiogenesis and vascular permeability by targeting prolyl hydroxylase and tight junction protein ZO-1. Oncogene 2017;36:4929-42. [Crossref] [PubMed]
62. Xiao X, Yu S, Li S, et al. Exosomes: decreased sensitivity of lung cancer A549 cells to cisplatin. PLoS One 2014;9:e89534. [Crossref] [PubMed]
63. Shukuya T, Ghai V, Amann JM, et al. Circulating MicroRNAs and Extracellular Vesicle-Containing MicroRNAs as Response Biomarkers of Anti-programmed Cell Death Protein 1 or Programmed Death-Ligand 1 Therapy in NSCLC. J Thorac Oncol 2020;15:1773-81. [Crossref] [PubMed]
64. Zhang JT, Qin H, Man Cheung FK, et al. Plasma extracellular vesicle microRNAs for pulmonary ground-glass nodules. J Extracell Vesicles 2019;8:1663666. [Crossref] [PubMed]
65. Jin X, Chen Y, Chen H, et al. Evaluation of Tumor-Derived Exosomal miRNA as Potential Diagnostic Biomarkers for Early-Stage Non-Small Cell Lung Cancer Using Next-Generation Sequencing. Clin Cancer Res 2017;23:5311-9. [Crossref] [PubMed]
66. Cazzoli R, Buttitta F, Di Nicola M, et al. microRNAs derived from circulating exosomes as noninvasive biomarkers for screening and diagnosing lung cancer. J Thorac Oncol 2013;8:1156-62. [Crossref] [PubMed]
67. Grimolizzi F, Monaco F, Leoni F, et al. Exosomal miR-126 as a circulating biomarker in non-small-cell lung cancer regulating cancer progression. Sci Rep 2017;7:15277. [Crossref] [PubMed]
68. Chen Q, Chen S, Zhao J, et al. MicroRNA-126: A new and promising player in lung cancer. Oncol Lett 2021;21:35. [Crossref] [PubMed]
69. Zhang Q, Zheng K, Gao Y, et al. Plasma exosomal miR-1290 and miR-29c-3p as diagnostic biomarkers for lung cancer. Heliyon 2023;9:e21059. [Crossref] [PubMed]
70. Han Z, Li Y, Zhang J, et al. Tumor-derived circulating exosomal miR-342-5p and miR-574-5p as promising diagnostic biomarkers for early-stage Lung Adenocarcinoma. Int J Med Sci 2020;17:1428-38. [Crossref] [PubMed]
71. Kim DH, Park S, Kim H, et al. Tumor-derived exosomal miR-619-5p promotes tumor angiogenesis and metastasis through the inhibition of RCAN1.4. Cancer Lett 2020;475:2-13. [Crossref] [PubMed]
72. Wei K, Ma Z, Yang F, et al. M2 macrophage-derived exosomes promote lung adenocarcinoma progression by delivering miR-942. Cancer Lett 2022;526:205-16. [Crossref] [PubMed]
73. Ma Z, Wei K, Yang F, et al. Tumor-derived exosomal miR-3157-3p promotes angiogenesis, vascular permeability and metastasis by targeting TIMP/KLF2 in non-small cell lung cancer. Cell Death Dis 2021;12:840. [Crossref] [PubMed]
74. Zhao K, Jia C, Wang J, et al. Exosomal hsa-miR-151a-3p and hsa-miR-877-5p are potential novel biomarkers for predicting bone metastasis in lung cancer. Aging (Albany NY) 2023;15:14864-88. [Crossref] [PubMed]
75. Fan J, Xu G, Chang Z, et al. miR-210 transferred by lung cancer cell-derived exosomes may act as proangiogenic factor in cancer-associated fibroblasts by modulating JAK2/STAT3 pathway. Clin Sci (Lond) 2020;134:807-25. [Crossref] [PubMed]
76. Yang F, Yan Y, Yang Y, et al. MiR-210 in exosomes derived from CAFs promotes non-small cell lung cancer migration and invasion through PTEN/PI3K/AKT pathway. Cell Signal 2020;73:109675. [Crossref] [PubMed]
77. He S, Li Z, Yu Y, et al. Exosomal miR-499a-5p promotes cell proliferation, migration and EMT via mTOR signaling pathway in lung adenocarcinoma. Exp Cell Res 2019;379:203-13. [Crossref] [PubMed]
78. Qi Y, Zha W, Zhang W. Exosomal miR-660-5p promotes tumor growth and metastasis in non-small cell lung cancer. J BUON 2019;24:599-607.
79. Zheng B, Peng M, Gong J, et al. Circulating exosomal microRNA-4497 as a potential biomarker for metastasis and prognosis in non-small-cell lung cancer. Exp Biol Med (Maywood) 2023;248:1403-13. [Crossref] [PubMed]
80. Yang C, Jia X, Zhou J, et al. The MiR-17-92 Gene Cluster is a Blood-Based Marker for Cancer Detection in Non-Small-Cell Lung Cancer. Am J Med Sci 2020;360:248-60. [Crossref] [PubMed]
81. Wu X, Cheng YL, Matthen M, et al. Down-regulation of the tumor suppressor miR-34a contributes to head and neck cancer by up-regulating the MET oncogene and modulating tumor immune evasion. J Exp Clin Cancer Res 2021;40:70. [Crossref] [PubMed]
82. Akbarzadeh M, Mihanfar A, Akbarzadeh S, et al. Crosstalk between miRNA and PI3K/AKT/mTOR signaling pathway in cancer. Life Sci 2021;285:119984. [Crossref] [PubMed]
83. Yuwen DL, Sheng BB, Liu J, et al. MiR-146a-5p level in serum exosomes predicts therapeutic effect of cisplatin in non-small cell lung cancer. Eur Rev Med Pharmacol Sci 2017;21:2650-8.
84. Rahbarghazi R, Jabbari N, Sani NA, et al. Tumor-derived extracellular vesicles: reliable tools for Cancer diagnosis and clinical applications. Cell Commun Signal 2019;17:73. [Crossref] [PubMed]
85. Statello L, Maugeri M, Garre E, et al. Identification of RNA-binding proteins in exosomes capable of interacting with different types of RNA: RBP-facilitated transport of RNAs into exosomes. PLoS One 2018;13:e0195969. [Crossref] [PubMed]
86. Villarroya-Beltri C, Baixauli F, Gutiérrez-Vázquez C, et al. Sorting it out: regulation of exosome loading. Semin Cancer Biol 2014;28:3-13. [Crossref] [PubMed]
87. Thakur BK, Zhang H, Becker A, et al. Double-stranded DNA in exosomes: a novel biomarker in cancer detection. Cell Res 2014;24:766-9. [Crossref] [PubMed]
88. Xiang Z, Xie Q, Yu Z. Exosomal DNA: Role in Reflecting Tumor Genetic Heterogeneity, Diagnosis, and Disease Monitoring. Cancers (Basel) 2023;16:57. [Crossref] [PubMed]
89. Jahani MM, Mashayekhi P, Omrani MD, et al. Assessing the Sensitivity of Nested PCR Followed by Direct Sequencing on Exosomal DNA for EGFR Mutation Detection in NSCL. Iran Biomed J 2024;28:208-15. [Crossref] [PubMed]
90. Brennan K, Martin K, FitzGerald SP, et al. A comparison of methods for the isolation and separation of extracellular vesicles from protein and lipid particles in human serum. Sci Rep 2020;10:1039. [Crossref] [PubMed]
91. Chen J, Li P, Zhang T, et al. Review on Strategies and Technologies for Exosome Isolation and Purification. Front Bioeng Biotechnol 2021;9:811971. [Crossref] [PubMed]
92. Liga A, Vliegenthart AD, Oosthuyzen W, et al. Exosome isolation: a microfluidic road-map. Lab Chip 2015;15:2388-94. [Crossref] [PubMed]
93. Moser AC, Hage DS. Immunoaffinity chromatography: an introduction to applications and recent developments. Bioanalysis 2010;2:769-90. [Crossref] [PubMed]
94. Rabinowits G, Gerçel-Taylor C, Day JM, et al. Exosomal microRNA: a diagnostic marker for lung cancer. Clin Lung Cancer 2009;10:42-6. [Crossref] [PubMed]
95. Rodríguez M, Silva J, López-Alfonso A, et al. Different exosome cargo from plasma/bronchoalveolar lavage in non-small-cell lung cancer. Genes Chromosomes Cancer 2014;53:713-24. [Crossref] [PubMed]
96. Zhong M, Zou M, Yao Y, et al. Induction and Modulation of EVs by Cigarette Smoke and Their Relevance in Lung Disease: Recent Advances. J Respir 2023;3:164-77.
97. Pastushenko I, Blanpain C. EMT Transition States during Tumor Progression and Metastasis. Trends Cell Biol 2019;29:212-26. [Crossref] [PubMed]
98. Vanni I, Alama A, Grossi F, et al. Exosomes: a new horizon in lung cancer. Drug Discov Today 2017;22:927-36. [Crossref] [PubMed]
99. Wojczakowski W, Kobylarek D, Lindner J, et al. MicroRNAs - novel biomarkers for malignant pleural effusions. Contemp Oncol (Pozn) 2019;23:133-40. [Crossref] [PubMed]
100. Pak MG, Shin DH, Lee CH, et al. Significance of EpCAM and TROP2 expression in non-small cell lung cancer. World J Surg Oncol 2012;10:53. [Crossref] [PubMed]
101. Prabhakar CN. Epidermal growth factor receptor in non-small cell lung cancer. Transl Lung Cancer Res 2015;4:110-8. [Crossref] [PubMed]
102. Muñiz-García A, Romero M, Falcόn-Perez JM, et al. Hypoxia-induced HIF1α activation regulates small extracellular vesicle release in human embryonic kidney cells. Sci Rep 2022;12:1443. [Crossref] [PubMed]
103. Lawson J, Dickman C, Towle R, et al. Extracellular vesicle secretion of miR-142-3p from lung adenocarcinoma cells induces tumor promoting changes in the stroma through cell-cell communication. Mol Carcinog 2019;58:376-87. [Crossref] [PubMed]
104. Zhuang G, Wu X, Jiang Z, et al. Tumour-secreted miR-9 promotes endothelial cell migration and angiogenesis by activating the JAK-STAT pathway. EMBO J 2012;31:3513-23. [Crossref] [PubMed]
105. Ye ZW, Yu ZL, Chen G, et al. Extracellular vesicles in tumor angiogenesis and resistance to anti-angiogenic therapy. Cancer Sci 2023;114:2739-49. [Crossref] [PubMed]
106. Ko SY, Lee W, Kenny HA, et al. Cancer-derived small extracellular vesicles promote angiogenesis by heparin-bound, bevacizumab-insensitive VEGF, independent of vesicle uptake. Commun Biol 2019;2:386. [Crossref] [PubMed]
107. Simon T, Pinioti S, Schellenberger P, et al. Shedding of bevacizumab in tumour cells-derived extracellular vesicles as a new therapeutic escape mechanism in glioblastoma. Mol Cancer 2018;17:132. [Crossref] [PubMed]
108. Zhang X, Sai B, Wang F, et al. Hypoxic BMSC-derived exosomal miRNAs promote metastasis of lung cancer cells via STAT3-induced EMT. Mol Cancer 2019;18:40. [Crossref] [PubMed]
109. Wang L, He J, Hu H, et al. Lung CSC-derived exosomal miR-210-3p contributes to a pro-metastatic phenotype in lung cancer by targeting FGFRL1. J Cell Mol Med 2020;24:6324-39. [Crossref] [PubMed]
110. Whiteside TL. Exosomes and tumor-mediated immune suppression. J Clin Invest 2016;126:1216-23. [Crossref] [PubMed]
111. Castillo-Peña A, Molina-Pinelo S. Landscape of tumor and immune system cells-derived exosomes in lung cancer: mediators of antitumor immunity regulation. Front Immunol 2023;14:1279495. [Crossref] [PubMed]
112. Kugeratski FG, Kalluri R. Exosomes as mediators of immune regulation and immunotherapy in cancer. FEBS J 2021;288:10-35. [Crossref] [PubMed]
113. Liang Y, Duan L, Lu J, et al. Engineering exosomes for targeted drug delivery. Theranostics 2021;11:3183-95. [Crossref] [PubMed]
114. Wang Y, Guo M, Lin D, et al. Docetaxel-loaded exosomes for targeting non-small cell lung cancer: preparation and evaluation in vitro and in vivo. Drug Deliv 2021;28:1510-23. [Crossref] [PubMed]
115. Lin X, Lin L, Wu J, et al. A targeted siRNA-loaded PDL1-exosome and functional evaluation against lung cancer. Thorac Cancer 2022;13:1691-702. [Crossref] [PubMed]
116. Xu Z, Liu X, Wang H, et al. Lung adenocarcinoma cell-derived exosomal miR-21 facilitates osteoclastogenesis. Gene 2018;666:116-22. [Crossref] [PubMed]