Interferons as therapeutic orchestrators of cancer stem cell plasticity and therapy response.

Cancer stem cells (CSCs) represent a small but critical subset of tumor cells characterized by their inherent self-renewal ability, differentiation potential, and resistance to cancer therapies. Their capacity to reversibly transition between a stem-like and differentiated state, together with their ability to enter into quiescence, are key determinants of their contribution to tumor initiation, tumor progression, metastasis, and cancer recurrence. Among the various factors in the tumor microenvironment, increasing evidence suggests that interferons (IFNs) are key extrinsic modulators of CSC fate. Although type I (IFN-α/β) and type II (IFN-γ) IFNs have long been recognized for their antitumor properties, recent studies indicate that IFN-signaling may also facilitate CSC induction and maintenance. In this review, we summarize and critically assess our current understanding of the complex roles of IFNs in governing CSC survival, plasticity, and immunogenicity. We discuss how IFN-signaling thresholds, signaling duration, and intrinsic CSC regulatory networks determine whether IFNs suppress CSCs or instead reinforce stemness. By bridging mechanistic insights with therapeutic potential and clinical outcomes, we highlight emerging opportunities to exploit IFN pathways for improved biomarkers and therapeutic strategies to overcome CSC-driven resistance.