Beyond Structural Classification: A 4S+G Functional Framework for Non-Coding RNA Biology in Cancer and Its Therapeutic Implications

Non-coding RNAs (ncRNAs) regulate gene expression at multiple levels in cancer, yet their functional plasticity and the slow pace of clinical translation remain incompletely explained. This review is organized around a unifying theme: ncRNAs act as integrative nodes connecting the epigenetic, transcriptional, signaling, and metabolic regulatory layers. Building on the established signal, sponge, scaffold, and guide archetypes of long non-coding RNA function, we extend this schema into a 4S+G model that adds a splice-regulatory archetype and embeds all five modes in a three-axis taxonomy spanning structural topology, subcellular localization, and molecular mode of operation, thereby capturing context-dependent functions that binary structural categories cannot accommodate. We dissect chromatin remodeling dynamics, evaluate the competing endogenous RNA hypothesis against stoichiometric evidence, and trace metabolic–epigenetic feedback circuits that stabilize malignant states. We then critically appraise the clinical record of ncRNA therapeutics, from the termination of MRX34 to the modest efficacy of subsequent candidates, and analyze the delivery, immunogenicity, and biomarker barriers that distinguish oncology from other indications for RNA drugs. Emerging solutions, including ligand-directed extrahepatic delivery, spatial transcriptomics, and deep learning-based target prediction, are assessed against these bottlenecks. The 4S+G framework links mechanistic understanding to a realistic roadmap for developing ncRNA-targeted cancer therapeutics with favorable risk–benefit profiles.