Long noncoding RNAs in tumor stemness: emerging mechanisms and therapeutic opportunities

Cancer stem cells (CSCs) constitute a subpopulation of malignant cells with self-renewal and differentiation capabilities that drive tumorigenicity, metabolic adaptability, immune evasion, and therapeutic resistance, key factors contributing to metastasis and poor clinical outcomes. While genetic drivers of tumorigenesis are well-characterized, the epigenetic machinery sustaining the CSC state remains complex. Long noncoding RNAs (lncRNAs) represent a vast yet poorly understood class of regulatory molecules that influence gene expression at epigenetic, transcriptional, and post-transcriptional levels. Emerging evidence indicates that lncRNAs play a crucial role in shaping tumor cell plasticity and stemness-associated phenotypes. In this mini-review, we summarize current findings on how lncRNAs regulate CSC biology. We categorize their mechanisms of action, ranging from chromatin remodeling to the modulation of mRNA and protein stability. Furthermore, we discuss how the advent of high-resolution omics, including bulk tissue, single-cell, and spatial transcriptomics studies, is revolutionizing the identification CSC-associated lncRNAs and contributing to the development of clinically relevant biomarkers. Finally, we explore advanced methodologies for manipulating lncRNA expression, assessing the challenges and opportunities of lncRNA-directed therapeutics as a novel strategy to dismantle tumor plasticity and overcome drug resistance.