Aug 2026· Genomics, Proteomics & Bioinformatics· 0 citations
Medicine
TL;DR
Current discoveries defining the lncRNA-TIME nexus are synthesized and advances in high-throughput sequencing, single-cell transcriptomics, and computational modeling that enable the mapping of these complex networks are highlighted.
Abstract
Long non-coding RNAs (lncRNAs) have emerged as pivotal regulators of tumor-immune interactions, bridging epigenetic, transcriptional, and post-transcriptional control of immune signaling networks. Recent multi-omics analyses reveal that lncRNAs shape the tumor immune microenvironment (TIME) by influencing immune-cell differentiation, activation, and exhaustion, as well as cytokine, chemokine, and immune-checkpoint pathways. Acting through molecular scaffolding, chromatin remodeling, and competing endogenous RNA (ceRNA) mechanisms, lncRNAs orchestrate the recruitment and functional polarization of lymphoid and myeloid populations, thereby dictating the balance between antitumor immunity and immune suppression. Integrative evidence further links specific lncRNA signatures to PD-1/PD-L1 checkpoint regulation, metabolic reprogramming, and therapeutic resistance. Here, we synthesize current discoveries defining the lncRNA-TIME nexus and highlight advances in high-throughput sequencing, single-cell transcriptomics, and computational modeling that enable the mapping of these complex networks. We discuss the translational promise of targeting lncRNAs as biomarkers and therapeutic nodes to enhance immunotherapy efficacy. Collectively, these integrative insights position lncRNAs as critical molecular interfaces connecting tumor genomics with immune regulation and open new avenues for precision immuno-oncology.
Metastasis and therapeutic resistance remain the principal causes of cancer-related mortality, reflecting the failure of current therapies to eradicate disseminated and treatment-refractory tumor cells. Long non-coding RNAs, once considered transcriptional noise, have now emerged as pivotal regulators of cancer progression, acting through diverse mechanisms to modulate signaling pathways, transcriptional programs, tumor metabolism, and the tumor microenvironment. Accumulating evidence demonstrates that lncRNAs orchestrate epithelial-mesenchymal transition, metabolic reprogramming, and immune evasion, thereby enabling metastatic dissemination and fostering resistance to chemotherapy. Moreover, recent discoveries have revealed that certain lncRNAs can encode functional micropeptides, further expanding their biological and therapeutic relevance. In this review, we systematically summarize current advances in lncRNA-mediated regulation of cancer metastasis and drug resistance, with particular emphasis on their roles in oncogenic signaling cascades, transcriptional control, immune cell reprogramming, and metabolic remodeling. we also discuss emerging therapeutic strategies targeting lncRNAs, including antisense oligonucleotides, CRISPR-based approaches, and lncRNA-encoded micropeptides interventions. Finally, we highlight key challenges, including context-dependent lncRNA functions, tumor heterogeneity, delivery, off-target effects, and biomarker standardization, and discuss multi-omics, single-cell, and spatial approaches may facilitate the translation of lncRNA biology into precision oncology.
Dong Liang, Jing-Wen Zheng, Zheng-Dan Gao et al.· Biochimica et biophysica act...· 0 citations
These findings call for a revised molecular dogma in which the noncoding genome is recognized as a major regulator of cellular function, oncogenic transformation, and immune surveillance.
Maria Lteif, Assia Hijazi, E. Morgand et al.· Oncoimmunology· 0 citations
This review examines how different types of ncRNAs contribute to cancer initiation, progression, and treatment resistance, and assesses their potential as diagnostic markers, prognostic factors, and therapeutic targets.
Akanksha Samuel, G. Calin· Carcinogenesis· 0 citations
As the stable and conserved circular non-coding RNAs, circular RNAs (circRNAs) have assumed growing significance in regulating breast cancer immunity and immunotherapy. This review focuses on elucidating the molecular mechanisms through which circRNAs influence the efficacy of breast cancer immunotherapy. Specifically, circRNAs modulate the levels and stability of critical immune checkpoints, including PD-L1 and various cytokines. They achieve this by acting as competing endogenous RNAs (ceRNAs) to sequester miRNAs, functioning as protein scaffolds, and thereby modulating gene expression and tumor immune evasion. Furthermore, circRNAs are capable of facilitating communication between tumor cells and immune cells. In addition, it can be translated into proteins that aid in remodeling the tumor immune microenvironment. These changes may include driving the polarization of immunosuppressive M2-type macrophages, while suppressing the infiltration and functional activity of cytotoxic T cells and natural killer cells. These findings highlight the significant promise of circRNAs serving as novel biomarkers and candidate therapeutic targets. Targeting specific circRNAs is anticipated to emerge as an effective approach for enhancing the efficacy of current immune checkpoint inhibitors, potentially helping to overcome drug resistance encountered in immunotherapy. Furthermore, it offers potential for the development of novel circRNA-based vaccines. Collectively, these advancements pave the way for improving the prognosis of breast cancer immunotherapy and open new avenues for future research and clinical translation.
Yu Jiang, Ya-Wen Wang, Kai Zhang· Frontiers in Immunology· 0 citations
New 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.
N. Elemam, Jana H. Sweillam, Youssef A. El-Sherif et al.· Frontiers in Immunology· 1 citation
Circular RNAs (circRNAs) are a class of highly stable non-coding RNAs that play pivotal roles in cancer progression by concurrently modulating tumor metastasis and immune evasion. Among them, a subset termed hub circRNAs coordinates these two processes within the same tumor context through multiple regulatory mechanisms. Hub circRNAs facilitate tumor cell migration, invasion, and colonization at distant sites, while simultaneously impairing the function of immune effector cells and remodeling the tumor microenvironment into an immunosuppressive state. These dual effects can be propagated to distal microenvironments via extracellular vesicles, thereby amplifying both metastasis and immunosuppression. To organize the available evidence, we propose a provisional three-tiered stringent/convergent/network-informed (S/C/N) evidence-mapping framework that integrates evidence across studies and organizes the type and completeness of functional, mechanistic, and network-informed support. Finally, we highlight current research gaps, outline the potential of hub circRNAs as biomarkers and therapeutic targets, and discuss experimental and methodological considerations for pan-cancer investigations. This review offers a functional perspective for understanding hub circRNAs as regulators linking metastasis with immune evasion and guides future efforts to investigate their dual functions in translational settings.
Jun-Yu Jia, Zhao-Kun Liu, Yu-Jie Zhao et al.· Frontiers in Immunology· 0 citations
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