Long non-coding RNAs as master regulators of cancer metastasis and therapeutic resistance.
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.