bims-exocan 2025-12-21 papers

bims-exocan

Biomed News

on Exosomes roles in cancer

Issue of 2025–12–21
nine papers selected by
Muhammad Rizwan, COMSATS University

Exosomal circRNAs in hepatocellular carcinoma: Implications for the development and therapeutic resistance of hepatocellular carcinoma (Review).
Breast cancer-derived exosomal miR-92a-3p stimulates malignant progression by driving TLR4/NF-κB-mediated macrophage M2 polarization.
Exosomal heterogeneity and functional zonation in cancer drug resistance.
Exosomes and NcRNAs in tumor: a comprehensive review and multi-perspective study.
Tumor cell exosome circ-0023919 promotes EMT through the miR-197-5p/ICAM5 axis and enhances the drug resistance of colorectal cancer to 5-Fu.
Crosstalk Between Extracellular Vesicles and Regulatory T Cells Across Cancers: From Interaction to Therapeutic Potential.
Engineered Plant-Derived Extracellular Vesicles as Targeted Drug Carriers in Cancer Therapy.
Crosstalk between tumor cells and tumor-associated macrophages mediated by extracellular vesicles: Research advances in remodeling the tumor microenvironment in colorectal cancer.
Exosomal miR-3126-5p derived from cancer-associated fibroblasts facilitates glycolysis to accelerate NSCLC progression by targeting KLF13 to activate the SH2B1/IRS1 axis.

Int J Oncol. 2026 Feb;pii: 26. [Epub ahead of print]68(2):

Exosomal circRNAs in hepatocellular carcinoma: Implications for the development and therapeutic resistance of hepatocellular carcinoma (Review).

Zhiyao Liu, Yuqiao Wang, Yali Wang, Yucheng Zhang.

  Hepatocellular carcinoma (HCC) is the predominant type of primary liver cancer, with high morbidity and mortality rates globally, ranking it among the leading causes of cancer‑related death worldwide. Despite notable advancements in HCC treatment in recent years, high rates of recurrence and treatment resistance remain significant clinical challenges. The development of drug resistance undermines the efficacy of current therapies and leads to poor patient outcomes. However, the specific role and detailed delivery mechanism of exosomal circular RNAs (circRNAs) in mediating this treatment resistance are still largely undefined. circRNAs represent a group of non‑coding RNAs with various biological roles. An increasing number of circRNAs are abnormally expressed in HCC and participate in the malignant progression of HCC, playing a role in HCC treatment resistance. Furthermore, circRNAs can exert additional effects when packaged into exosomes. Exosomes, as signaling molecules of intercellular communication, are enriched with circRNAs, which can be packaged, secreted and transferred to target recipient tumor cells, thereby regulating the development process and drug resistance of cancer. The present comprehensive review aims to summarize how these exosomal circRNAs regulate key hallmarks of cancer in HCC and critically synthesize the current literature, elucidating how exosomal circRNAs modulate therapeutic resistance in HCC and highlighting their potential as biomarkers and therapeutic targets.

Keywords:  circular RNAs; exosomes; hepatocellular carcinoma; therapy resistance

DOI:  https://doi.org/10.3892/ijo.2025.5839
Biochem Biophys Res Commun. 2025 Dec 11. pii: S0006-291X(25)01840-6. [Epub ahead of print]795 153124

Breast cancer-derived exosomal miR-92a-3p stimulates malignant progression by driving TLR4/NF-κB-mediated macrophage M2 polarization.

Sheng Ding, Jian Wang, Jing Pei.

  Breast cancer (BC) cell-derived exosomes significantly reshape the tumor microenvironment; however, the key mechanisms driving tumor progression remain unclear. This study employed transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blotting to analyze exosomes from MCF-10A normal breast epithelial cells and MDA-MB-231/MCF-7 breast cancer cells. Treatment of parental BC cells with tumor-derived exosomes markedly enhanced malignant characteristics, whereas exosomes from miR-92a-3p-knockdown cells reversed these malignant phenotypes. Bioinformatics analysis of the EVMiRNA database initially identified miR-92a-3p as the most prominently upregulated miRNA in blood exosomes from BC patients. This finding was validated by qRT-PCR, which demonstrated significant overexpression of miR-92a-3p in tumor-derived exosomes. Exosomal miR-92a-3p induced immunosuppressive M2 polarization of THP-1-derived macrophages, evidenced by upregulated mRNA levels of Arg-1, Ym1, and IL-10, an increased proportion of CD206+cells; and elevated IL-10 secretion accompanied by reduced TNF-α secretion. Mechanistically, the TLR4/NF-κB pathway in macrophages was activated by parental exosomes, resulting in increased expression of TLR4 and phosphorylated p65, whereas miR-92a-3p-knockdown exosomes inhibited this pathway activation. Importantly, we confirmed that miR-92a-3p directly targets the 3'untranslated region (3'UTR) of TLR4 using a luciferase reporter assay. In conclusion, tumor-derived exosomal miR-92a-3p exerts dual effects: it directly enhances the invasiveness of BC cells and promotes M2 polarization by activating the TLR4/NF-κB axis in macrophages, thereby accelerating tumor progression. These findings highlight the pivotal role of miR-92a-3p in tumor-exosome crosstalk and identify it as a promising therapeutic target for BC.

Keywords:  Breast cancer; Exosomes; M2 macrophage polarization; TLR4/NF-κB pathway; miR-92a-3p

DOI:  https://doi.org/10.1016/j.bbrc.2025.153124
Drug Discov Today. 2025 Dec 17. pii: S1359-6446(25)00300-9. [Epub ahead of print] 104587

Exosomal heterogeneity and functional zonation in cancer drug resistance.

Shikshya Swarupa Panda, Rajeev Kumar Sahoo, Sambit Kumar Patra, Sachidananda Behera, Ashish Kumar Khamari, Bijesh Kumar Biswal.

  Exosomes are nanoscale extracellular vesicles that mediate critical intercellular communication within the tumor microenvironment (TME). Recent advancements reveal that exosome populations within tumors are not uniform but exhibit significant heterogeneity in their molecular cargo and functional output. This heterogeneity is particularly pronounced in spatially organized tumors, where distinct functional zones, driven by gradients in local stress, perfusion, and metabolic states, orchestrate the release of unique exosome subtypes. These functional zones include stromal, hypoxic, perivascular, quiescent, and immune-cold regions. The zone-specific exosomes deliver specialized molecular cargos, including nucleic acids, proteins, lipids, and metabolites, to recipient cells within the TME and at distant sites. This communication promotes tumor sustenance and contributes to drug resistance through diverse mechanisms, such as immune suppression, epithelial-mesenchymal transition (EMT), metabolic reprogramming, and the activation of prosurvival signaling pathways. Although bulk exosome analysis has enabled the development of biomarkers for personalized medicine, it often fails to capture these intricate, zone-specific influences. This review explores emerging techniques, including single-cell sequencing, microchip-based 3D tumor cultures, advanced spectroscopic methods, and spatial biology platforms, that are poised to elucidate the spatiotemporal communication networks mediated by zonal exosomes, thereby advancing the understanding of drug resistance mechanisms.

Keywords:  cancer; drug resistance; exosomes; spatial heterogeneity

DOI:  https://doi.org/10.1016/j.drudis.2025.104587
Int J Surg. 2025 Dec 16.

Exosomes and NcRNAs in tumor: a comprehensive review and multi-perspective study.

Xiaoman Zhang, Dequan Liu, Xiaochen Qi, Xinming Zhao, Shijin Wang, Guandu Li, Xiaoxin Cheng, Xu Zheng, Guangzhen Wu.

  In this paper, the multiple functions of exosomes and their non-coding RNA (ncRNAs) in maintaining homeostasis and promoting disease progression were systematically discussed. Exosomes, as the key carriers of intercellular communication, can be widely involved in physiological and pathological processes such as immune regulation, tissue repair, angiogenesis, metabolic reprogramming and TME shaping by transmitting bioactive molecules such as protein, lipids and ncRNAs. Especially in the field of tumor, exocrine ncRNAs (such as miRNA, lncRNA and circRNA) affect tumor occurrence, metastasis, drug resistance and immune escape through competitive endogenous RNA (ceRNA) mechanism, signal pathway regulation and epigenetic modification. In addition, exosomes show great potential in liquid biopsy and targeted drug delivery, providing new biomarkers and strategies for cancer diagnosis and treatment. However, the standardization of exosomes application, targeting efficiency and drug resistance mechanism are still challenges for future research. To sum up, the study of exosomes and ncRNAs not only deepens the understanding of disease mechanism, but also opens up a new way for developing precision medical tools.

Keywords:  drug resistance; exosomes; metabolism; ncRNAs; tumor

DOI:  https://doi.org/10.1097/JS9.0000000000004418
Exp Cell Res. 2025 Dec 13. pii: S0014-4827(25)00466-5. [Epub ahead of print] 114866

Tumor cell exosome circ-0023919 promotes EMT through the miR-197-5p/ICAM5 axis and enhances the drug resistance of colorectal cancer to 5-Fu.

Jingjing Zhang, Yuanxiang Wu, Yaping Wang, Huihui Zeng.

  5-Fluorouracil (5-Fu) is a cornerstone chemotherapeutic agent in the treatment of colorectal cancer (CRC). However, its clinical efficacy is frequently hampered by the development of drug resistance, which remains a major obstacle to successful treatment. The aim of this study is to gain a comprehensive understanding of the role and mechanism of the tumor cell-derived exosomal circ-0023919 in 5-Fu resistance. High-throughput microarray technology was employed to identify differentially expressed circRNAs in 5-Fu resistance CRC cells and their derived exosomes. A CRC/5-Fu drug-resistant cell line was successfully established using the drug gradient induction method, and its resistance index was subsequently determined. We employed transmission electron microscopy, nanoparticle tracking analysis (NTA) and Western blot to characterize exosomes by detecting the exosomal markers CD63 and TSG101. The circular structure, stability, and subcellular localization of circ-0023919 were confirmed using a combination of approaches, including actinomycin D treatment, RNase R digestion, specific primer PCR amplification, Sanger sequencing and FISH. Furthermore, we systematically evaluated the regulatory role of circ-0023919 in multiple biological functions of CRC cells by assessing cell proliferation, migration, invasion, drug resistance, stemness and EMT-related markers. Our findings demonstrate that circ-0023919 promotes the migration and invasion of CRC/5-Fu cells both in vitro and in vivo, while also enhancing resistance to 5-Fu chemotherapy. Mechanistically, circ-0023919 acts as a molecular sponge for miR-197-5p, thereby upregulating the expression of ICAM5. In this scientific study, circ-0023919 is shown to enhance the resistance of CRC cells to 5-Fu by promoting EMT. Thus, circ-0023919 is considered a potential therapeutic target for CRC treatment.

Keywords:  CRC/5-Fu; EMT; ICAM5; circ-0023919; miR-197-5p

DOI:  https://doi.org/10.1016/j.yexcr.2025.114866
Int J Nanomedicine. 2025 ;20 14643-14665

Crosstalk Between Extracellular Vesicles and Regulatory T Cells Across Cancers: From Interaction to Therapeutic Potential.

Di Liu, Zhixiong Hao, Guangpeng He, Ye Huang.

  Regulatory T cells (Treg cells) play a crucial role in maintaining immune tolerance and regulating immune responses, especially in cancer, where their immunosuppressive function is highly significant. Treg cells accumulate in the tumor microenvironment (TME), interact with tumor cells and other immune cells, and suppress anti-tumor immunity through various mechanisms, including secretion of immunosuppressive cytokines, direct contact with target cells, and depletion of key nutrients and signaling molecules. Regulating Treg cells has become a novel approach for enhancing cancer immunotherapy. Extracellular vesicles (EVs) are small vesicles with a lipid bilayer membrane secreted by all cells and play an important role in tumor biology as communication mediators by transmitting proteins, RNA, and other bioactive molecules in TME. In the past years, an increasing amount of research has uncovered the effects of EVs on Treg in TME, greatly enriching our understanding of Treg in tumor progression. Additionally, due to the potential of EVs as "natural nanoparticles" for drug and gene delivery, targeting Treg via an EV-delivery system has become a hotspot. Therefore, we comprehensively summarized the updates on the effects of EVs on Treg in TME and EV-related therapy for tumor treatment.

Keywords:  extracellular vesicle; immunotherapy; regulatory T cells; tumor microenvironment

DOI:  https://doi.org/10.2147/IJN.S562593
ACS Appl Bio Mater. 2025 Dec 16.

Engineered Plant-Derived Extracellular Vesicles as Targeted Drug Carriers in Cancer Therapy.

Su Jin Kang, Won Jong Rhee.

  Breast cancer remains one of the most prevalent and deadly cancers worldwide, with many patients experiencing limited treatment efficacy and adverse side effects from conventional chemotherapy. These limitations are primarily due to poor drug targeting, low bioavailability, and systemic toxicity. To address these challenges, extracellular vesicles (EVs) have emerged as promising drug delivery systems owing to their innate biocompatibility, cellular delivery capabilities, and ability to carry diverse bioactive molecules. Among various EV sources, plant-derived EVs offer unique advantages, including low immunogenicity, cost-effective scalability, and absence of animal-derived components, making them highly suitable for clinical applications. In this study, we developed a plant-derived EV-based drug delivery platform using black soybean-derived extracellular vesicles (Blex). A high yield of Blex was successfully purified from black soybean and subsequently loaded with a substantial amount of chemotherapeutic agent doxorubicin (Dox) through passive diffusion. To achieve tumor-targeting specificity, Blex were chemically engineered by covalently conjugating the cyclic RGD (cRGD) peptide, which binds to integrin receptors overexpressed in many cancer types, including breast cancer. The resulting Dox-loaded Blex engineered with cancer cell-targeting cRGD (Blex(Dox)_cRGD) demonstrated enhanced cellular uptake, improved cytotoxicity against breast cancer cells, and greater tumor reduction in vivo. This work highlights the potential of combining drug loading with surface engineering to improve therapeutic outcomes while minimizing systemic toxicity. Overall, our findings underscore the utility of plant-derived EVs as a scalable, biocompatible platform for targeted chemotherapy. This strategy provides a foundation for next-generation nanomedicine development, offering a therapeutic approach for breast cancer and other solid tumors.

Keywords:  black soybean-derived extracellular vesicles; cancer therapy; drug delivery; extracellular vesicles; plant-derived extracellular vesicles

DOI:  https://doi.org/10.1021/acsabm.5c01943
Crit Rev Oncol Hematol. 2025 Dec 12. pii: S1040-8428(25)00467-6. [Epub ahead of print]218 105079

Crosstalk between tumor cells and tumor-associated macrophages mediated by extracellular vesicles: Research advances in remodeling the tumor microenvironment in colorectal cancer.

Dadi Shu, Zhaoming Chen, Baolin Li, Jing Wei, Jinbo Liu, Qiongying Hu.

  Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide and ranks third in incidence among all cancer types. Among the treatment strategies for CRC, immunotherapy-particularly approaches targeting modulation of the tumor microenvironment (TME) to prevent immune escape-represents a key component. The interaction and influence between CRC cells and tumor-associated macrophages (TAMs) within the TME have been shown to be closely associated with immune escape and malignant progression in CRC. Among them, extracellular vesicles (EVs) derived from CRC cells (CRC-EVs) can be taken up by TAMs in the TME and regulate their polarization as well as the production of related bioactive substances. Conversely, EVs secreted by TAMs (TAMs-EVs) can be internalized by CRC cells, thereby promoting the malignant biological behaviors, including proliferation, metastasis, and resistance to radiotherapy and chemotherapy. In this review, we focus on the crosstalk between CRC cells and TAMs within the TME, summarizing and integrating current evidence on how CRC-EVs and TAMs-EVs contribute to TME remodeling and thereby influence CRC malignancy, while systematically outlining the cellular signaling pathways involved in this bidirectional communication.

Keywords:  Colorectal cancer; Crosstalk; Extracellular vesicles; Tumor microenvironment; Tumor-associated macrophages

DOI:  https://doi.org/10.1016/j.critrevonc.2025.105079
Clin Transl Med. 2025 Dec;15(12): e70554

Exosomal miR-3126-5p derived from cancer-associated fibroblasts facilitates glycolysis to accelerate NSCLC progression by targeting KLF13 to activate the SH2B1/IRS1 axis.

Zhenyu Zhang, Haicheng Ma, Yingying Zheng, Lina Wang, Chenghui Wang, Yuanyuan Liu, Hengxiao Lu, Shaoqiang Wang.

   BACKGROUND: As a critical component of the tumour microenvironment, cancer-associated fibroblasts (CAFs) actively drive the malignant advancement of non-small-cell lung cancer (NSCLC); however, their underlying mechanisms continue to be poorly characterized. This work examined the role of CAFs-derived exosomal miR-3126-5p in the glycolysis of NSCLC cells.
METHODS: Glycolysis was evaluated by lactate production, glucose uptake, oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). Cell proliferation and cycle were evaluated by CCK-8, EdU staining, and flow cytometry. Src homology 2B adaptor protein 1 (SH2B1) and insulin receptor substrate 1 (IRS1) protein interaction was tested by Co-IP and GST pull-down assay. ChIP, dual-luciferase reporter assay, and EMSA determined the binding of kruppel-like factor 13 (KLF13) to the SH2B1 promoter. Dual-luciferase reporter assay was applied to assess miR-3126-5p binding to KLF13 3'-UTR. In vivo growth of NSCLC was determined in the mouse xenograft and Lewis lung carcinoma models.
RESULTS: CAFs-derived exosomal miR-3126-5p was highly expressed in NSCLC tissues, and its elevated plasma level was significantly associated with poor prognosis of NSCLC patients. CAFs-derived exosomal miR-3126-5p facilitated glycolysis to accelerate the malignant progression of NSCLC cells. KLF13 exhibited reduced expression in NSCLC, while its overexpression suppressed NSCLC growth via repressing glycolysis. Exosomal miR-3126-5p targeted KLF13 3'-UTR to inhibit its expression in NSCLC cells. KLF13 transcriptionally inhibited SH2B1 expression to abolish the interaction between SH2B1 and IRS1 proteins, thus repressing PI3K/AKT pathway-mediated glycolysis. KLF13 knockdown counteracted the anti-cancer action of exosomal miR-3126-5p inhibition.
CONCLUSION: CAFs-derived exosomal miR-3126-5p accelerated NSCLC progression via inhibiting KLF13 expression, which transcriptionally activated SH2B1 to promote its interaction with IRS1, thereby promoting PI3K/AKT pathway-mediated glycolysis. Our findings position CAFs-secreted exosomal miR-3126-5p as a novel therapeutic intervention with potential in NSCLC management.
HIGHLIGHTS: CAFs-derived exosomal miR-3126-5p enhanced glycolysis of NSCLC cells via targeting KLF13. KLF13 led to transcriptional inhibition of SH2B1 in NSCLC cells. SH2B1 interplayed with IRS1 to facilitate glycolysis of NSCLC cells. IRS1 promoted glycolysis of NSCLC cells via the activation of PI3K/AKT pathway.

Keywords:  KLF13; SH2B1; cancer‐associated fibroblasts; exosomal miR‐3126‐5p; glycolysis; non‐small‐cell lung cancer

DOI:  https://doi.org/10.1002/ctm2.70554