Non-Coding RNAs as key regulators of interferon signaling in cancer immunotherapy: mechanistic insights and clinical prospects

Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), play vital, context-specific roles in cancer, functioning as either tumor suppressors or oncogenic factors. Preliminary evidence suggests that a primary mechanism of ncRNA influence is through the interferon (IFN) signaling pathway, with a focus on how they may regulate IFN-induced immune surveillance and immunotherapy outcomes. Types I, II, and III IFNs regulate antitumor immunity, antigen presentation, and immune checkpoint activity, but can also support tumor growth in certain scenarios. Evidence indicates ncRNAs modulate IFN signaling by targeting IFN receptors, JAK-STAT components, interferon-stimulated genes (ISGs), and IRFs. Some ncRNAs suggest potential to enhance antitumor immune responses and improve responses to IFN-based therapies, while others may dampen immune activity, contribute to therapy resistance, or promote metastasis. This review centers on how ncRNAs act as tumor suppressors or promoters through modulating IFN signaling to influence immunotherapy efficacy, demonstrating their versatile roles in shaping immune surveillance across various cancers. Although encouraging, experimental findings face challenges like functional complexity, delivery barriers, and off-target effects that must be addressed before clinical application. By integrating mechanistic and translational perspectives, this review highlights potential new opportunities to target ncRNA-IFN interactions for personalized medicine and advanced immunotherapies.