<p>Cancer remains a major global health challenge. Current diagnostic and therapeutic strategies are often limited by the complexity and heterogeneity of the disease. Long non-coding RNAs (lncRNAs) have recently emerged as important regulators of cancer. They influence tumor initiation, progression, metastasis, immune evasion, and therapy resistance. This review summarizes the clinical significance of lncRNAs and their potential as tools for cancer diagnosis, prognosis, and treatment. We describe their molecular functions, including interactions with DNA, RNA, and proteins, and explain how they regulate oncogenic pathways, contribute to drug resistance, and modulate immune responses. We also highlight the translational potential of lncRNAs as diagnostic and prognostic biomarkers, as well as therapeutic targets in multiple cancer types. Completed and ongoing clinical trials further support their relevance, particularly in cancer immunotherapy and lncRNA-based vaccine development. Despite these advances, important challenges remain. Efficient delivery, target specificity, and robust clinical validation are still major hurdles. Emerging strategies aim to address these issues and improve the clinical feasibility of lncRNA-based approaches. By integrating current molecular insights with clinical progress, this review underscores the promise of lncRNAs in oncology. They hold significant potential to advance precision medicine and shape future directions in cancer management.</p> Graphical Abstract