Aug 2026· Cancer Biome and Targeted Therapy· pp. 252-281· 0 citations· 113 references
TL;DR
Current evidence is synthesized on how exosomal ncRNAs orchestrate immune-metabolic networks that shape TNBC evolution and their emerging clinical applications as liquid biopsy biomarkers for diagnosis, prognostic stratification, and therapeutic monitoring, as well as their potential as therapeutic targets via antisense oligonucleotides (ASOs), antagomirs, and engineered exosome-based delivery platforms.
Abstract
Triple-negative breast cancer (TNBC) is characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression, limiting the applicability of endocrine and HER2-targeted therapies. Clinically, TNBC exhibits marked molecular heterogeneity, aggressive behavior, early metastatic dissemination, and poor prognosis relative to other breast cancer subtypes. Increasing evidence indicates that the tumor microenvironment (TME) plays a central role in TNBC progression and therapeutic resistance, with exosomes serving as key mediators of intercellular communication. Exosomes, extracellular vesicles measuring 30–150 nm in diameter, are enriched in non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), which regulate interconnected signaling pathways governing proliferation, apoptosis, invasion, epithelial-mesenchymal transition (EMT), angiogenesis, immune evasion, metabolic reprogramming, and therapy resistance. This review synthesizes current evidence on how exosomal ncRNAs orchestrate immune-metabolic networks that shape TNBC evolution and highlights their emerging clinical applications as liquid biopsy biomarkers for diagnosis, prognostic stratification, and therapeutic monitoring, as well as their potential as therapeutic targets via antisense oligonucleotides (ASOs), antagomirs, and engineered exosome-based delivery platforms. Finally, we discuss current translational challenges, including exosome heterogeneity, analytical standardization, and clinical validation, and outline future directions for integrating exosomal ncRNAs into precision management strategies for TNBC.
Extracellular vesicle (EV)-associated non-coding RNAs (ncRNAs) are increasingly recognized as mediators of intercellular communication within the tumor microenvironment (TME), yet their mechanistic and translational significance varies substantially across gastrointestinal and hepatobiliary cancers. This narrative review, informed by a structured literature search, integrates evidence on EV-associated microRNAs, long non-coding RNAs, and circular RNAs in esophageal, gastric, colorectal, pancreatic, hepatocellular carcinoma, and cholangiocarcinoma. Rather than organizing the literature by RNA class or individual tumor type, we synthesize findings according to major TME functions, including immune remodeling, cancer-associated fibroblast activation, vascular remodeling, paracrine tumor-cell reprogramming, therapy resistance, and tumor-suppressive vesicular signaling. Recurrent mechanisms involve PTEN/PI3K/AKT, JAK/STAT, TGF-β/Smad, Wnt/β-catenin, and immune-checkpoint pathways, but the strength of evidence differs markedly among studies. Accordingly, mechanistic findings are distinguished from animal-model-supported, clinically correlated, preliminary, and biomarker-only evidence using a standardized descriptive framework. The review also highlights cholangiocarcinoma as an underrepresented but increasingly informative hepatobiliary model while avoiding generalization to broader biliary tract cancers when direct evidence is lacking. Major barriers to clinical translation include inconsistent EV isolation and characterization, uncertain vesicle-source attribution, limited validation of recipient-cell transfer and causal targets, small retrospective cohorts, and insufficient prospective validation. Overall, EV-ncRNAs represent promising mechanistic biomarkers and therapeutic targets, but rigorous source-specific validation and standardized analytical workflows are required before clinical implementation.
T. Alramadneh, Waleed K. Abdulsahib, Sanan Thaer Abdal-Wahab et al.· Cancer Treatment and Researc...· 0 citations
Breast cancer remains a major health concern among women, characterized by a high risk and substantial mortality. Chemotherapy is widely employed as a standard treatment modality to eliminate malignant cells and improve patient survival. Nevertheless, recurrence and chemoresistance arising from taxane treatment have emerged as key factors driving the high mortality rates in cancer patients. Non-coding RNAs (ncRNAs), encompassing microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), represent a key functional output of the human genome and, via intricate regulatory networks, influence nearly all facets of cancer biology, including the development of chemoresistance. Importantly, in taxane-resistant breast cancer cells, the identified miRNAs displayed bifunctional roles: some promoted resistance, whereas others enhanced sensitivity. This functional duality is also observed in lncRNAs, highlighting their context‑dependent regulatory roles. Additionally, ncRNAs are enriched in taxane-resistant cells-derived exosomes, where they play a crucial role in spreading taxane resistance and chemotherapy failure through genetic modulation of taxane‑sensitive cells. Notably, targeting ncRNAs via various therapeutic approaches, including herbal compounds and synthetic peptides, has shown hopeful findings in reversing taxane resistance in breast cancer, highlighting a promising avenue for the management of taxane resistance in breast cancer.
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract and are usually driven by activating mutations in KIT or PDGFRA. Although these alterations define the core molecular biology of GISTs and guide targeted therapy, they do not fully explain the variability observed in tumor behavior, recurrence risk, or response to tyrosine kinase inhibitors. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), have been increasingly studied as regulators of gene expression in GISTs. Recent evidence suggests that these molecules may influence KIT-centered signaling, autophagy, apoptosis, invasion, angiogenesis, and drug resistance. However, the strength of evidence differs considerably across individual ncRNAs, ranging from bioinformatic associations to functional validation in cell lines and in vivo models. This review summarizes current knowledge on ncRNA-mediated regulation in GIST biology, with emphasis on tumor progression, therapeutic resistance, and possible clinical relevance. Rather than treating ncRNAs as isolated biomarkers, they function as part of broader regulatory networks that interact with oncogenic signaling and epigenetic mechanisms. Although several ncRNAs appear promising as prognostic or predictive candidates, further validation in independent clinical cohorts is required before their integration into routine risk stratification or treatment decision-making.
Georgios Mandrakis, Stavros P. Papadakos, Georgia Levidou et al.· International Journal of Mol...· 0 citations
Triple-negative breast cancer (TNBC) is an aggressive and clinically heterogeneous breast cancer subtype characterized by the absence of estrogen receptor, progesterone receptor, and HER2 overexpression, limited targeted treatment options, early relapse, and frequent development of therapy resistance. Although TNBC often shows initial sensitivity to chemotherapy, durable responses are commonly undermined by the emergence of adaptive resistant cell states rather than solely by fixed genetic mutations. This review synthesizes the role of epigenetic plasticity as a central mechanism that enables TNBC cells to dynamically reprogram transcriptional identity, survive therapeutic stress, and transition between epithelial, mesenchymal, stem-like, immune-evasive, and drug-tolerant persister phenotypes. Key epigenetic mechanisms include aberrant DNA methylation, histone acetylation and methylation, BET/BRD4-dependent transcriptional regulation, EZH2-mediated repression, SWI/SNF-dependent chromatin remodeling, non-coding RNA networks, and three-dimensional genome reorganization. These processes regulate tumor suppressor silencing, DNA-damage repair, epithelial–mesenchymal plasticity, cancer stem-cell maintenance, metabolic adaptation, immune-checkpoint regulation, and minimal residual disease. The review also highlights the translational relevance of epigenetic biomarkers, including DNA methylation signatures, circulating epigenetic markers, chromatin-accessibility profiles, and single-cell epigenomic approaches for diagnosis, prognosis, therapy prediction, and monitoring resistance evolution. Finally, therapeutic strategies targeting epigenetic plasticity are discussed, including DNMT, HDAC, BET, EZH2, KDM, and LSD1 inhibitors, with emphasis on rational combination approaches involving chemotherapy, PARP inhibitors, immunotherapy, and metabolic targeting. Overall, epigenetic plasticity represents both a major driver of TNBC resistance and a therapeutically exploitable vulnerability, provided those future strategies account for tumor heterogeneity, adaptive cell-state transitions, biomarker-guided patient selection, and combination-based treatment design.
A. Alaa, Salma A. B. El-Din, Mohannad A. Farrag et al.· Biomedicines· 0 citations
Glioblastoma (GBM) is the most aggressive primary malignant brain tumor in adults and remains associated with poor clinical outcomes despite advances in surgical resection, radiotherapy, and temozolomide-based chemotherapy. Its remarkable molecular heterogeneity, highly immunosuppressive tumor microenvironment, and intrinsic therapeutic resistance continue to limit the effectiveness of current treatment strategies. Long non-coding RNAs (lncRNAs), transcripts exceeding 200 nucleotides in length that lack protein-coding capacity, have emerged as critical regulators of GBM biology through transcriptional, post-transcriptional, and epigenetic mechanisms. Acting as competing endogenous RNAs, chromatin modifiers, molecular scaffolds, and regulators of RNA-binding proteins, lncRNAs orchestrate key oncogenic pathways controlling proliferation, invasion, angiogenesis, stemness, metabolic reprogramming, immune evasion, and resistance to chemotherapy and radiotherapy. This review provides a comprehensive overview of lncRNA biogenesis, classification, and mechanisms of action, followed by an updated synthesis of oncogenic and tumor-suppressive lncRNAs implicated in GBM progression. Particular emphasis is placed on emerging evidence demonstrating how immunophenotype-related lncRNAs regulate immune cell infiltration, immune checkpoint signaling, and the immunosuppressive glioblastoma microenvironment, highlighting their potential to improve patient stratification and guide immunotherapeutic approaches. We also discuss the growing clinical utility of lncRNAs as diagnostic, prognostic, and predictive biomarkers, including circulating lncRNAs and lncRNA-based molecular signatures. Finally, we examine current and emerging therapeutic strategies targeting lncRNAs, including nanoparticle-mediated delivery systems designed to overcome the blood-brain barrier. Advances in single-cell and spatial transcriptomic technologies are further expanding our understanding of lncRNA-mediated regulatory networks and intratumoral heterogeneity, supporting the development of precision medicine strategies. Collectively, lncRNAs represent promising biomarkers and therapeutic targets with significant potential to improve the diagnosis, prognosis, and treatment of glioblastoma.
N. Elemam, Jana H. Sweillam, Youssef A. El-Sherif et al.· Frontiers in Immunology· 1 citation
Abstract Lung cancer remains the leading cause of cancer-related mortality worldwide, with chemoresistance being a major challenge in its treatment. Long non-coding RNAs (lncRNAs), a class of transcripts longer than 200 nucleotides without protein-coding potential, have emerged as critical regulators in tumour progression and drug resistance. This review systematically summarizes the multifaceted mechanisms through which lncRNAs influence chemoresistance across major lung cancer subtypes, particularly non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), including regulation of cell proliferation, cell cycle progression, migration, invasion, apoptosis, pyroptosis, necroptosis, and autophagy. Some key lncRNAs function as competing endogenous RNAs (ceRNAs) to sponge microRNAs, modulate chromatin architecture, or alter key signalling pathways (eg, PI3K/Akt, Wnt/β-catenin, and JAK2/STAT3), ultimately promoting survival and chemoresistance of lung cancer cells under chemotherapeutic stress. Clarification of these mechanisms provides novel insights into the development of early diagnostic markers and therapeutic targets. Future research should focus on elucidating specific lncRNA interactions, developing lncRNA-based therapeutics, and exploring their roles in tumour microenvironments and drug-resistant subpopulations to overcome chemoresistance.
Maodan Hou, Jiangyu Chen, Peng Yi et al.· Cancer Management and Resear...· 0 citations
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