Non-coding RNAs at the intersection of interferon signaling and cancer: mechanistic insights and clinical prospects

Interferon (IFN) signaling plays a vital role in influencing tumor outcomes, acting as a switch between immune control and evasion based on the situation. When IFN responses are acute and well-regulated, they enhance processes such as antigen processing, dendritic cell activation, cytotoxic lymphocyte response, and the activation of interferon-stimulated genes (ISGs), which lead to cell cycle arrest and programmed cell death. Conversely, prolonged or dysfunctional IFN signaling can be exploited by tumors, resulting in immunoediting, increased checkpoint molecule expression, T-cell exhaustion, stress tolerance, and resistance to therapy and metastasis. The tumor microenvironment (TME) affects this dual role by influencing immune cell infiltration, stromal and blood vessel behavior, and metabolic constraints. Non-coding RNAs (ncRNAs)-including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs)-add an extra regulatory layer by modulating IFN induction, JAK-STAT signaling, IRF/STAT-driven gene transcription, and ISG programming. There exists a bidirectional relationship: tumor-suppressive ncRNAs enhance IFN responses and immunogenicity, whereas oncogenic ncRNAs can suppress signaling and facilitate immune escape. The discussion also explores compartment-specific effects within the TME, links to epithelial-mesenchymal transition (EMT) and metastatic plasticity, and the potential of ncRNAs as biomarkers, therapeutic targets, and the challenges in translating these insights into clinical practice.